Therapeutic inhibitory compounds

ABSTRACT

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds that are useful for inhibiting plasma kallikrein. Furthermore, the subject compounds and compositions are useful for the treatment of diseases wherein the inhibition of plasma kallikrein inhibition has been implicated, such as angioedema and the like.

CROSS-REFERENCE

This application is a U.S. National Phase Application of InternationalApplication No. PCT/US2014/072851, filed Dec. 30, 2014, which claimspriority to U.S. Provisional Application No. 62/025,203, filed Jul. 16,2014, and claims priority to U.S. Provisional Application No.61/921,995, filed Dec. 30, 2013, all of which are incorporated herein byreference in their entirety.

BACKGROUND

A need exists in the medicinal arts for the effective treatment ofdiseases and disorders related to the vascular system. Such diseases anddisorders include, but are not limited to, angioedema, macular edema andbrain edema.

BRIEF SUMMARY OF THE INVENTION

Provided herein are heterocyclic derivative compounds and pharmaceuticalcompositions comprising said compounds. The subject compounds andcompositions are useful for inhibiting plasma kallikrein.

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (I):

wherein,

-   -   Ring A is an optionally substituted bicyclic heteroaryl ring;    -   Ring B is an optionally substituted monocyclic heteroaryl ring        or optionally substituted bicyclic heteroaryl ring;    -   each R¹², R¹³, or R¹⁴ is independently selected from hydrogen,        cyano, halo, hydroxy, azido, amino, nitro, —CO₂H, —S(O)—R²⁰,        —S—R²⁰, —S(O)₂—R²⁰, optionally substituted alkoxy, optionally        substituted aryloxy, optionally substituted heteroaryloxy,        optionally substituted (heterocyclyl)-O—, optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        alkenyl, optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocyclyl, optionally        substituted alkylamino, optionally substituted dialkylamino,        —CO—R²⁰, —CO₂—R²⁰, —CO(NR²¹)₂, —SO₂(NR²¹)₂, —C(═NR²²)—(NR²¹)₂,        or optionally substituted alkynyl;    -   each R¹ or R² is independently selected from hydrogen, halo,        hydroxy, amino, —CO₂H, —S(O)—R²⁰, —S—R²⁰, —S(O)₂—R²⁰, optionally        substituted alkoxy, optionally substituted aryloxy, optionally        substituted heteroaryloxy, optionally substituted        (heterocyclyl)-O—, optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted alkenyl,        optionally substituted aryl, optionally substituted heteroaryl,        optionally substituted heterocyclyl, optionally substituted        alkylamino, optionally substituted dialkylamino, —CO—R²⁰,        —CO₂—R²⁰, —CO(NR²¹)₂, —SO₂(NR²¹)₂, —C(═NR²²)—(NR²¹)₂, or        optionally substituted alkynyl; or optionally, R¹ and R² are        optionally substituted C1-C5 alkyl and join to form a ring; or        optionally, R¹ and R² together form an oxo;    -   each R³ or R⁴ is independently selected from hydrogen, —CO₂H,        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted alkenyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, —CO—R²⁰, —CO₂—R²⁰, —CO(NR²¹)₂, —SO₂(NR²¹)₂,        —C(═NR²²)—(NR²¹)₂, or optionally substituted alkynyl; or        optionally, R³ and R⁴ are optionally substituted C1-C5 alkyl and        join to form a ring;    -   each R²⁰ is selected from optionally substituted alkyl,        optionally substituted cycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl, or optionally substituted        heterocyclyl;    -   each R²¹ is selected from hydrogen, optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl, or optionally        substituted heterocyclyl; and    -   each R²² is selected from hydrogen, —CN, optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl, or optionally        substituted heterocyclyl; with the provision that the compound        of Formula (I) is not        2-[[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]methyl]-N-(2-thienylmethyl)-4-pyridinecarboxamide.

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ia):

wherein,

-   -   Ring A is an optionally substituted bicyclic heteroaryl ring;        and    -   Ring B is an optionally substituted monocyclic heteroaryl ring        or optionally substituted bicyclic heteroaryl ring; with the        provision that the compound of Formula (Ia) is not        2-[[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]methyl]-N-(2-thienylmethyl)-4-pyridinecarboxamide.

One embodiment provides a pharmaceutical composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

One embodiment provides a method of inhibiting kallikrein enzymecomprising contacting the kallikrein enzyme with a compound of Formula(I).

One embodiment provides a method for treating angioedema in a patient inneed thereof comprising administering to the patient a compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

One embodiment provides a pharmaceutical composition comprising acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

One embodiment provides a method of inhibiting kallikrein enzymecomprising contacting the kallikrein enzyme with a compound of Formula(Ia).

One embodiment provides a method for treating angioedema in a patient inneed thereof comprising administering to the patient a compositioncomprising a compound of Formula (Ia), or a pharmaceutically acceptablesalt thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference for the specificpurposes identified herein.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange, in some instances, will vary between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) is not intendedto exclude that in other certain embodiments, for example, an embodimentof any composition of matter, composition, method, or process, or thelike, described herein, “consist of” or “consist essentially of” thedescribed features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅alkyl). In other embodiments, the alkyl group is selected from methyl,ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)— N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)— N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl comprises two to six carbonatoms. In other embodiments, an alkynyl comprises two to four carbonatoms. The alkynyl is attached to the rest of the molecule by a singlebond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, andthe like. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group isthrough one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)— N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon triple bond, and having from two to twelve carbon atoms.The alkynylene chain is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. In certainembodiments, an alkynylene comprises two to eight carbon atoms (e.g.,C₂-C₈ alkynylene). In other embodiments, an alkynylene comprises two tofive carbon atoms (e.g., C₂-C₅ alkynylene). In other embodiments, analkynylene comprises two to four carbon atoms (e.g., C₂-C₄ alkynylene).In other embodiments, an alkynylene comprises two to three carbon atoms(e.g., C₂-C₃ alkynylene). In other embodiments, an alkynylene comprisestwo carbon atom (e.g., C₂ alkylene). In other embodiments, an alkynylenecomprises five to eight carbon atoms (e.g., C₅-C₈ alkynylene). In otherembodiments, an alkynylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkynylene). Unless stated otherwise specifically in thespecification, an alkynylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)— N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O) R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl is saturated (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds). A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O) R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkynyl” refers to a radical of the formula—R^(c)-carbocyclyl where R^(c) is an alkynylene chain as defined above.The alkynylene chain and the carbocyclyl radical is optionallysubstituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Insome embodiments, the alkyl part of the fluoroalkyl radical isoptionally substituted as defined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, whichoptionally includes fused or bridged ring systems. The heteroatoms inthe heterocyclyl radical are optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl is attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O) R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O) R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein, in some embodiments, contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R)— or (S)—. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein, in certain embodiments, exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

The compounds disclosed herein, in some embodiments, are used indifferent enriched isotopic forms, e.g., enriched in the content of ²H,³H, ¹¹C, ¹³C and/or ¹⁴C. In one particular embodiment, the compound isdeuterated in at least one position. Such deuterated forms can be madeby the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Asdescribed in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration canimprove the metabolic stability and or efficacy, thus increasing theduration of action of drugs.

Unless otherwise stated, structures depicted herein are intended toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of the present disclosure.

The compounds of the present disclosure optionally contain unnaturalproportions of atomic isotopes at one or more atoms that constitute suchcompounds. For example, the compounds may be labeled with isotopes, suchas for example, deuterium (²H), tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C). Isotopic substitution with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N,¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S,³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁵I are all contemplated. All isotopicvariations of the compounds of the present invention, whetherradioactive or not, are encompassed within the scope of the presentinvention.

In certain embodiments, the compounds disclosed herein have some or allof the ¹H atoms replaced with ²H atoms. The methods of synthesis fordeuterium-containing compounds are known in the art and include, by wayof non-limiting example only, the following synthetic methods.

Deuterium substituted compounds are synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr, Pharm. Des., 2000; 6(10)] 2000, 110 pp;George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compoundsvia Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21;and Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64(1-2), 9-32.

Deuterated starting materials are readily available and are subjected tothe synthetic methods described herein to provide for the synthesis ofdeuterium-containing compounds. Large numbers of deuterium-containingreagents and building blocks are available commerically from chemicalvendors, such as Aldrich Chemical Co.

Deuterium-transfer reagents suitable for use in nucleophilicsubstitution reactions, such as iodomethane-d₃ (CD₃I), are readilyavailable and may be employed to transfer a deuterium-substituted carbonatom under nucleophilic substitution reaction conditions to the reactionsubstrate. The use of CD₃I is illustrated, by way of example only, inthe reaction schemes below.

Deuterium-transfer reagents, such as lithium aluminum deuteride(LiAlD₄), are employed to transfer deuterium under reducing conditionsto the reaction substrate. The use of LiAlD₄ is illustrated, by way ofexample only, in the reaction schemes below.

Deuterium gas and palladium catalyst are employed to reduce unsaturatedcarbon-carbon linkages and to perform a reductive substitution of arylcarbon-halogen bonds as illustrated, by way of example only, in thereaction schemes below.

In one embodiment, the compounds disclosed herein contain one deuteriumatom. In another embodiment, the compounds disclosed herein contain twodeuterium atoms. In another embodiment, the compounds disclosed hereincontain three deuterium atoms. In another embodiment, the compoundsdisclosed herein contain four deuterium atoms. In another embodiment,the compounds disclosed herein contain five deuterium atoms. In anotherembodiment, the compounds disclosed herein contain six deuterium atoms.In another embodiment, the compounds disclosed herein contain more thansix deuterium atoms. In another embodiment, the compound disclosedherein is fully substituted with deuterium atoms and contains nonon-exchangeable ¹H hydrogen atoms. In one embodiment, the level ofdeuterium incorporation is determined by synthetic methods in which adeuterated synthetic building block is used as a starting material.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the kallikreininhibitory compounds described herein is intended to encompass any andall pharmaceutically suitable salt forms. Preferred pharmaceuticallyacceptable salts of the compounds described herein are pharmaceuticallyacceptable acid addition salts and pharmaceutically acceptable baseaddition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are, in some embodiments, prepared by contacting the free baseforms with a sufficient amount of the desired acid to produce the saltaccording to methods and techniques with which a skilled artisan isfamiliar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts are, insome embodiments, formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. See Berge et al., supra.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are, in some embodiments,administered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease has not been made.

“Prodrug” is meant to indicate a compound that is, in some embodiments,converted under physiological conditions or by solvolysis to abiologically active compound described herein. Thus, the term “prodrug”refers to a precursor of a biologically active compound that ispharmaceutically acceptable. A prodrug is typically inactive whenadministered to a subject, but is converted in vivo to an activecompound, for example, by hydrolysis. The prodrug compound often offersadvantages of solubility, tissue compatibility or delayed release in amammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985),pp. 7-9, 21-24 (Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, are prepared by modifying functional groups present inthe active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

Kallikrein Inhibitory Compounds

Provided herein are heterocyclic derivative compounds and pharmaceuticalcompositions comprising said compounds. The subject compounds andcompositions are useful for inhibiting plasma kallikrein.

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (I):

wherein,

-   -   Ring A is an optionally substituted bicyclic heterocyclic or        heteroaryl ring;    -   Ring B is an optionally substituted monocyclic heterocyclic or        heteroaryl ring or optionally substituted bicyclic heterocyclic        or heteroaryl ring;    -   each R¹², R¹³, or R¹⁴ is independently selected from hydrogen,        cyano, halo, hydroxy, azido, amino, nitro, —CO₂H, —S(O)—R²⁰,        —S—R²⁰, —S(O)₂—R²⁰, optionally substituted alkoxy, optionally        substituted aryloxy, optionally substituted heteroaryloxy,        optionally substituted (heterocyclyl)-O—, optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        alkenyl, optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocyclyl, optionally        substituted alkylamino, optionally substituted dialkylamino,        —CO—R²⁰, —CO₂—R²⁰, —CO(NR²¹)₂, —SO₂(NR²¹)₂, —C(═NR²²)—(NR²¹)₂,        or optionally substituted alkynyl;    -   each R¹ or R² is independently selected from hydrogen, halo,        hydroxy, amino, —CO₂H, —S(O)—R²⁰, —S—R²⁰, —S(O)₂—R²⁰, optionally        substituted alkoxy, optionally substituted aryloxy, optionally        substituted heteroaryloxy, optionally substituted        (heterocyclyl)-O—, optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted alkenyl,        optionally substituted aryl, optionally substituted heteroaryl,        optionally substituted heterocyclyl, optionally substituted        alkylamino, optionally substituted dialkylamino, —CO—R²⁰,        —CO₂—R²⁰, —CO(NR²¹)₂, —SO₂(NR²¹)₂, —C(═NR²²)—(NR²¹)₂, or        optionally substituted alkynyl; or optionally, R¹ and R² are        optionally substituted C1-C5 alkyl and join to form a ring; or        optionally, R¹ and R² together form an oxo;    -   each R³ or R⁴ is independently selected from hydrogen, —CO₂H,        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted alkenyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, —CO—R²⁰, —CO₂—R²⁰, —CO(NR²¹)₂, —SO₂(NR²¹)₂,        —C(═NR²²)—(NR²¹)₂, or optionally substituted alkynyl; or        optionally, R³ and R⁴ are optionally substituted C1-C5 alkyl and        join to form a ring;    -   each R²⁰ is selected from optionally substituted alkyl,        optionally substituted cycloalkyl, optionally substituted aryl,        optionally substituted heteroaryl, or optionally substituted        heterocyclyl;    -   each R²¹ is selected from hydrogen, optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl, or optionally        substituted heterocyclyl; and    -   each R²² is selected from hydrogen, —CN, optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl, or optionally        substituted heterocyclyl; with the provision that the compound        of Formula (I) is not        2-[[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]methyl]-N-(2-thienylmethyl)-4-pyridinecarboxamide.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), whereinRing A is an optionally substituted bicyclic heterocyclic ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), whereinRing A is an optionally substituted bicyclic heteroaryl ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), whereinRing B is an optionally substituted monocyclic heterocyclic ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), whereinRing B is an optionally substituted monocyclic heteroaryl ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), whereinRing B is an optionally substituted bicyclic heterocyclic ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), whereinRing B is an optionally substituted bicyclic heteroaryl ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), whereinR¹² is hydrogen.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), whereinR¹⁴ is independently selected from —S(O)—R²⁰, —S—R²⁰, —S(O)₂—R²⁰,optionally substituted alkoxy, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted(heterocyclyl)-O—, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted alkylamino, optionallysubstituted dialkylamino, —CO—R²⁰, —CO₂—R²⁰, —CO(NR²¹)₂, —SO₂(NR²¹)₂, or—C(═NR²²)—(NR²¹)₂. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I), wherein R¹⁴ is independently selected from optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, or optionallysubstituted alkynyl. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I), wherein R¹⁴ is hydrogen. Another embodiment provides thecompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (I), wherein R¹⁴ is optionally substituted alkyl,or optionally substituted cycloalkyl.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), whereinR¹³ is independently selected from —S(O)—R²⁰, —S—R²⁰, —S(O)₂—R²⁰,optionally substituted alkoxy, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted(heterocyclyl)-O—, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted alkylamino, optionallysubstituted dialkylamino, —CO—R²⁰, —CO₂—R²⁰, —CO(NR²¹)₂, —SO₂(NR²¹)₂, or—C(═NR²²)—(NR²¹)₂. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I), wherein R¹³ is independently selected from optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, or optionallysubstituted alkynyl. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I), wherein R¹³ is hydrogen. Another embodiment provides thecompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (I), wherein R¹³ is optionally substituted alkyl,or optionally substituted cycloalkyl.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), wherein R³and R⁴ are hydrogen. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I), wherein R³ is hydrogen. Another embodiment provides thecompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (I), wherein R⁴ is hydrogen. Another embodimentprovides the compound, or a pharmaceutically acceptable salt thereof,having the structure of Formula (I), wherein R³ is optionallysubstituted alkyl. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I), wherein R⁴ is optionally substituted alkyl.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), wherein R¹and R² are hydrogen. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I), wherein R¹ is hydrogen. Another embodiment provides thecompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (I), wherein R² is hydrogen. Another embodimentprovides the compound, or a pharmaceutically acceptable salt thereof,having the structure of Formula (I), wherein R¹ is optionallysubstituted alkyl. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I), wherein R² is optionally substituted alkyl. Anotherembodiment provides the compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (I), wherein R¹ is optionallysubstituted alkoxy. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I), wherein R² is optionally substituted alkoxy.

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ia):

wherein,

-   -   Ring A is an optionally substituted bicyclic heterocyclic or        heteroaryl ring; and    -   Ring B is an optionally substituted monocyclic heterocyclic or        heteroaryl ring or optionally substituted bicyclic heterocyclic        or heteroaryl ring; with the provision that the compound of        Formula (I) is not        2-[[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]methyl]-N-(2-thienylmethyl)-4-pyridinecarboxamide.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (Ia), whereinRing A is an optionally substituted bicyclic heterocyclic ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (Ia), whereinRing A is an optionally substituted bicyclic heteroaryl ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (Ia), whereinRing B is an optionally substituted monocyclic heterocyclic ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (Ia), whereinRing B is an optionally substituted monocyclic heteroaryl ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (Ia), whereinRing B is an optionally substituted bicyclic heterocyclic ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (Ia), whereinRing B is an optionally substituted bicyclic heteroaryl ring.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I) or (Ia),wherein Ring B is not thiophenyl.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I) or (Ia),wherein Ring A is not tetrahydro-1H-indazol-1-yl.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I) or (Ia),wherein Ring A is selected from optionally substituted quinolyl,optionally substituted indolyl, optionally substituted indazolyl,optionally substituted benzimidazolyl, optionally substitutedisoquinolyl, optionally substituted cinnolinyl, optionally substitutedphthalazinyl, optionally substituted quinazolinyl, optionallysubstituted naphthyridinyl, or optionally substituted benzoisoxazolyl.Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I) or (Ia),wherein Ring A is selected from optionally substitutedbenzo[d]isoxazol-7-yl, optionally substituted 4-aminoquinazolin-5-yl,optionally substituted indol-5-yl; optionally substituted quinolin-3-yl;quinoxalin-2-yl; optionally substituted isoquinolin-1(2H)-on-2-yl; oroptionally substituted quinolin-6-yl. Another embodiment provides thecompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (I) or (Ia), wherein Ring A is an optionallysubstituted quinolin-6-yl. Another embodiment provides the compound, ora pharmaceutically acceptable salt thereof, having the structure ofFormula (I) or (Ia), wherein the optionally substituted quinolin-6-yl issubstituted with at least one substituent selected from optionallysubstituted C1-C3 alkyl, halogen, —CN, —SO₂Me, —SO₂NH₂, —CONH₂,—CH₂NHAc, —CO₂Me, —CO₂H, —CH₂OH, —CH₂NH₂, —NH₂, —OH, or —OMe. Anotherembodiment provides the compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (I) or (Ia), wherein theoptionally substituted quinolin-6-yl is substituted at least at the3-position. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I) or (Ia), wherein the quinolin-6-yl is selected from3-chloroquinolin-6-yl, 3-methylquinolin-6-yl,3-trifluoromethylquinolin-6-yl, 3-fluoroquinolin-6-yl, or3-cyanoquinolin-6-yl. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I) or (Ia), wherein Ring A is an optionally substitutedquinolin-3-yl. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I) or (Ia), wherein the optionally substituted quinolin-3-yl issubstituted at least at the 6-position or the 7-position. Anotherembodiment provides the compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (I) or (Ia), wherein theoptionally substituted quinolin-3-yl is substituted with at least onesubstituent selected from optionally substituted C1-C3 alkyl, halogen,—CN, —SO₂Me, —SO₂NH₂, —CONH₂, —CH₂NHAc, —CO₂Me, —CO₂H, —CH₂OH, —CH₂NH₂,—NH₂, —OH, or —OMe.

Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I) or (Ia),wherein Ring B is selected from an optionally substituted monocyclicheteroaryl ring. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I) or (Ia), wherein the optionally substituted monocyclicheteroaryl ring is selected from optionally substituted imidazolyl,optionally substituted pyrazolyl, optionally substituted pyridinyl,optionally substituted pyridazinyl, optionally substituted pyrimidinyl,or optionally substituted pyrazinyl. Another embodiment provides thecompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (I) or (Ia), wherein the optionally substitutedmonocyclic heteroaryl ring is an optionally substituted pyridinyl.Another embodiment provides the compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I) or (Ia),wherein the optionally substituted pyridinyl is an optionallysubstituted aminopyridinyl. Another embodiment provides the compound, ora pharmaceutically acceptable salt thereof, having the structure ofFormula (I) or (Ia), wherein the optionally substituted aminopyridinylis an optionally substituted 6-aminopyridin-3-yl. Another embodimentprovides the compound, or a pharmaceutically acceptable salt thereof,having the structure of Formula (I) or (Ia), wherein Ring B is selectedfrom an optionally substituted bicyclic heteroaryl ring. Anotherembodiment provides the compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (I) or (Ia), wherein theoptionally substituted bicyclic heteroaryl ring is selected fromoptionally substituted quinolinyl, optionally substituted isoquinolinyl,optionally substituted quinazolinyl, optionally substituted indolyl,optionally substituted indazolyl, optionally substituted1H-pyrrolo[2,3-b]pyridinyl, optionally substituted benzoxazolyl,optionally substituted benzoisoxazolyl, or optionally substitutedbenzimidazolyl. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I) or (Ia), wherein the optionally substituted bicyclicheteroaryl ring is an optionally substituted indolyl. Another embodimentprovides the compound, or a pharmaceutically acceptable salt thereof,having the structure of Formula (I) or (Ia), wherein the optionallysubstituted bicyclic heteroaryl ring is an optionally substitutedindazolyl. Another embodiment provides the compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I) or (Ia), wherein the optionally substituted indolyl is anoptionally substituted indol-5-yl. Another embodiment provides thecompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (I) or (Ia), wherein the optionally substitutedindazolyl is an optionally substituted indazol-5-yl. Another embodimentprovides the compound, or a pharmaceutically acceptable salt thereof,having the structure of Formula (I) or (Ia), wherein the optionallysubstituted bicyclic heteroaryl ring is an optionally substituted1H-pyrrolo[2,3-b]pyridinyl. Another embodiment provides the compound, ora pharmaceutically acceptable salt thereof, having the structure ofFormula (I) or (Ia), wherein Ring A is selected from optionallysubstituted quinolyl; and Ring B is selected from an optionallysubstituted indolyl, an optionally substituted indazolyl, and anoptionally substituted 1H-pyrrolo[2,3-b]pyridinyl.

In some embodiments, the kallikrein inhibitory compound described inFormula (I) has a structure provided in Table 1.

TABLE 1 Chemical Synthesis Example Structure Name 1

6-((4-(((3-chloro-6-fluoro-1H-indol-5- yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2-carboxamide 2

6-((4-(((6-amino-2,4-dimethylpyridin-3- yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2-carboxamide 3

N-((1-aminoisoquinolin-6-yl)methyl)-2-((2-cyanoquinolin-6-yl)methyl)isonicotinamide 4

6-((4-(((1-aminoisoquinolin-6- yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2-carboxamide 5

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((3-cyanoquinolin-6-yl)methyl)isonicotinamide 6

N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-cyanoquinolin-6-yl)methyl)isonicotinamide 7

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-cyanoquinolin-6-yl)methyl)isonicotinamide 8

N-((1-aminoisoquinolin-6-yl)methyl)-2-((7- fluoroquinoxalin-2-yl)methyl)isonicotinamide 9

2-((2-(acetamidomethyl)quinolin-6-yl)methyl)-N-((3-chloro-6-fluoro-1H-indol- 5-yl)methyl)isonicotinamide10

2-((2-(acetamidomethyl)quinolin-6- yl)methyl)-N-((1-aminoisoquinolin-6-yl)methyl)isonicotinamide 11

2-((2-(acetamidomethyl)quinolin-6- yl)methyl)-N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)isonicotinamide 12

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-(methylsulfonyl)quinolin-3- yl)methyl)isonicotinamide13

N-((1-aminoisoquinolin-6-yl)methyl)-2-((6- (methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide 14

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6-(methylsulfonyl)quinolin-3- yl)methyl)isonicotinamide15

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 16

N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 17

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 18

N-((6-fluoro-1H-indol-5-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 19

N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 20

N-((5-chloro-1H-indazol-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 21

N-((3-chloro-4-fluoro-1H-indol-5- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 22

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-chloro-1-oxoisoquinolin-2(1H)-yl)methyl)isonicotinamide 23

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6-chloro-1-oxoisoquinolin-2(1H)-yl)methyl)isonicotinamide 24

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-chloro-1H-indol-5-yl)methyl)isonicotinamide 25

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-methyl-1H-indol-5-yl)methyl)isonicotinamide 26

N-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide 27

2-amino-5-((2-((3-chloroquinolin-6- yl)methyl)isonicotinamido)methyl)-6-methylnicotinamide 28

N-((6-amino-5-chloro-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide 29

N-((6-amino-4-methylpyridin-3-yl)methyl)- 2-((3-chloroquinolin-6-yl)methyl)isonicotinamide 30

N-((6-amino-2-(trifluoromethyl)pyridin-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide 31

N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide 32

2-((3-chloroquinolin-6-yl)methyl)-N-((6- fluoro-1H-indazol-5-yl)methyl)isonicotinamide 33

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide 34

N-((6-amino-2-methylpyridin-3-yl)methyl)- 2-((3-chloroquinolin-6-yl)methyl)isonicotinamide 35

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide 36

N-((3-aminobenzo[d]isoxazol-6-yl)methyl)- 2-((3-chloroquinolin-6-yl)methyl)isonicotinamide 37

N-((5-chloro-1H-indazol-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide 38

N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide 39

N-((6-amino-2-methylpyridin-3-yl)methyl)- 2-((3-chloroquinolin-6-yl)methyl)isonicotinamide 40

N-((3-chloro-4-fluoro-1H-indol-5- yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide 41

2-((3-chloroquinolin-6-yl)methyl)-N-((6- fluoro-1H-indol-5-yl)methyl)isonicotinamide 42

2-((3-chloroquinolin-6-yl)methyl)-N-((2-methyl-6-(methylamino)pyridin-3- yl)methyl)isonicotinamide 43

N-((6-amino-2-cyclopropylpyridin-3- yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide 44

2-((3-chloroquinolin-6-yl)methyl)-N-((6-(dimethylamino)-2-methylpyridin-3- yl)methyl)isonicotinamide 45

2-((2-(aminomethyl)quinolin-6-yl)methyl)-N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)isonicotinamide 46

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2-(aminomethyl)quinolin-6- yl)methyl)isonicotinamide 47

N-((3-aminobenzo[d]isoxazol-6-yl)methyl)- 2-((3-methylquinolin-6-yl)methyl)isonicotinamide 48

N-((3-aminobenzo[d]isoxazol-6-yl)methyl)- 2-((6-methylquinolin-3-yl)methyl)isonicotinamide 49

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6- yl)methyl)isonicotinamide 50

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6- yl)methyl)isonicotinamide 51

N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6- yl)methyl)isonicotinamide 52

2-((3-chloro-8-cyanoquinolin-6-yl)methyl)- N-((6-fluoro-1H-indol-5-yl)methyl)isonicotinamide 53

N-((6-amino-4-methylpyridin-3-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6- yl)methyl)isonicotinamide 54

N-((5-chloro-1H-indazol-3-yl)methyl)-2-((3- chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide 55

N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6- yl)methyl)isonicotinamide 56

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6- yl)methyl)isonicotinamide 57

N-((1-aminoisoquinolin-6-yl)methyl)-2-((3- chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide 58

6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide 59

3-chloro-6-((4-(((3-chloro-6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2- yl)methyl)quinoline-8-carboxamide60

3-chloro-6-((4-(((5-chloro-1H-indazol-3- yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide 61

3-chloro-6-((4-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide 62

6-((4-(((6-amino-2-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide 63

6-((4-(((6-amino-4-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide 64

6-((4-(((1-aminoisoquinolin-6- yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide 65

3-chloro-6-((4-(((3-chloro-4-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2- yl)methyl)quinoline-8-carboxamide66

3-chloro-6-((4-(((6-fluoro-1H-indol-5- yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide 67

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 68

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 69

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 70

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((8-cyano-3-methylquinolin-6- yl)methyl)isonicotinamide 71

N-((1-aminoisoquinolin-6-yl)methyl)-2-((8- cyano-3-methylquinolin-6-yl)methyl)isonicotinamide 72

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6- yl)methyl)isonicotinamide 73

N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6- yl)methyl)isonicotinamide 74

N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6- yl)methyl)isonicotinamide 75

N-((5-chloro-1H-indazol-3-yl)methyl)-2-((8- cyano-3-methylquinolin-6-yl)methyl)isonicotinamide 76

2-((8-cyano-3-methylquinolin-6-yl)methyl)- N-((6-fluoro-1H-indol-5-yl)methyl)isonicotinamide 77

6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 78

6-((4-(((3-chloro-6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 79

6-((4-(((1-aminoisoquinolin-6- yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 80

6-((4-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamoyl)pyridin-2- yl)methyl)-3-methylquinoline-8-carboxamide 81

6-((4-(((3-chloro-4-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 82

6-((4-(((5-chloro-1H-indazol-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 83

6-((4-(((6-fluoro-1H-indol-5- yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 84

6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)- 3-methylquinoline-8-carboxylicacid 85

N-((6-amino-4-methylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)- yl)methyl)isonicotinamide 86

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)- yl)methyl)isonicotinamide 87

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide 88

2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)-N-((3-chloro-6-fluoro-1H-indol- 5-yl)methyl)isonicotinamide89

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6- yl)methyl)isonicotinamide 90

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6- yl)methyl)isonicotinamide 91

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6- yl)methyl)isonicotinamide 92

methyl 6-((4-(((6-amino-2,4- dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylate 93

6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)- 3-chloroquinoline-8-carboxylicacid 94

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-chloro-8-(hydroxymethyl)quinolin-6- yl)methyl)isonicotinamide 95

methyl 6-((4-(((6-amino-2-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylate 96

6-((4-(((6-amino-2-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)- 3-chloroquinoline-8-carboxylicacid 97

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-8-(hydroxymethyl)quinolin-6- yl)methyl)isonicotinamide 98

6-amino-3-((2-((3-chloroquinolin-6-yl)methyl)isonicotinamido)methyl)-2,4- dimethylpyridine 1-oxide 99

6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)- 3-chloroquinoline 1-oxide 100

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3,8-dichloroquinolin-6- yl)methyl)isonicotinamide 101

N-((6-amino-2-methylpyridin-3-yl)methyl)- 2-((3,8-dichloroquinolin-6-yl)methyl)isonicotinamide 102

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-5-fluoroquinolin-6- yl)methyl)isonicotinamide103

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-5-fluoroquinolin-6- yl)methyl)isonicotinamide 104

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-6-methylisonicotinamide 105

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((5-chloro-1H-indazol-1-yl)methyl)isonicotinamide 106

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinamide 107

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((5-methyl-2H-indazol-2-yl)methyl)isonicotinamide 108

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((5-methyl-1H-indazol-1-yl)methyl)isonicotinamide 109

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((6-methyl-2-(methylsulfonyl)quinolin-3- yl)methyl)isonicotinamide 110

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide 111

N-((1-aminoisoquinolin-6-yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide 112

N-((6-amino-2-methylpyridin-3-yl)methyl)- 2-((2-methylquinolin-6-yl)methyl)isonicotinamide 113

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide 114

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamide 115

N-((1-aminoisoquinolin-6-yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamide 116

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamide 117

N-((6-amino-2-methylpyridin-3-yl)methyl)- 2-((6-methylquinolin-3-yl)methyl)isonicotinamide 118

N-((1-aminoisoquinolin-6-yl)methyl)-2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide 119

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide 120

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide 121

N-((6-amino-2-methylpyridin-3-yl)methyl)- 2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide 122

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((7-fluoroquinolin-3-yl)methyl)isonicotinamide 123

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((7-fluoroquinolin-3-yl)methyl)isonicotinamide 124

N-((1-aminoisoquinolin-6-yl)methyl)-2-((7-fluoroquinolin-3-yl)methyl)isonicotinamide 125

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-(quinolin-3-ylmethyl)isonicotinamide 126

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((6-chloroquinolin-3-yl)methyl)isonicotinamide 127

N-((1-aminoisoquinolin-6-yl)methyl)-2-((2-methylquinolin-7-yl)methyl)isonicotinamide 128

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((2-methylquinolin-7-yl)methyl)isonicotinamide 129

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((2-methylquinolin-7-yl)methyl)isonicotinamide 130

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((2-isocyanoquinolin-6-yl)methyl)isonicotinamide 131

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((2-isocyanoquinolin-6-yl)methyl)isonicotinamide 132

N-((1-aminoisoquinolin-6-yl)methyl)-2-((3- methylisoquinolin-6-yl)methyl)isonicotinamide 133

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((3-methylisoquinolin-6-yl)methyl)isonicotinamide 134

N-((1-aminoisoquinolin-6-yl)methyl)-2-((2- (methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide 135

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide136

N-((1-aminoisoquinolin-6-yl)methyl)-2-((4-cyanoquinolin-6-yl)methyl)isonicotinamide 137

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((4-cyanoquinolin-6-yl)methyl)isonicotinamide 138

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((4-cyanoquinolin-6-yl)methyl)isonicotinamide 139

N-((1-aminoisoquinolin-6-yl)methyl)-2-((7-chloroquinolin-3-yl)methyl)isonicotinamide 140

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((7-chloroquinolin-3-yl)methyl)isonicotinamide 141

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((7-chloroquinolin-3-yl)methyl)isonicotinamide 142

N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide 143

N-((3-chloro-6-fluoro-1H-indol-5- yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide 144

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide 145

N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-methylisoquinolin-6-yl)methyl)isonicotinamide 146

N-((1-aminoisoquinolin-6-yl)methyl)-2-((2- (aminomethyl)quinolin-6-yl)methyl)isonicotinamide

In some embodiments, the compound described herein has the structureprovided in Table 2.

TABLE 2 Name Structure N-((1-aminoisoquinolin-6- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((6- cyanoquinolin-3-yl)methyl)isonicotinamide

3-((4-(((1- aminoisoquinolin-6- yl)methyl)carbamoyl)pyridin-2-yl)methyl) quinoline-6-carboxamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((6- chloroquinolin-3-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((6- (hydroxymethyl)quinolin-3-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((6- (aminomethyl)quinolin-3-yl)methyl)isonicotinamide

6-((4-(((1- aminoisoquinolin-6- yl)methyl)carbamoyl)pyridin-2-yl)methyl) quinoline-3-carboxamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((3- (hydroxymethyl)quinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((3- (aminomethyl)quinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((3-methyl-8-sulfamoylquinolin-6- yl)methyl)isonicotinamide

6-((4-(((1- aminoisoquinolin-6- yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3- methylquinoline-8- carboxylic acid

N-((6-amino-2- methylpyridin-3- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-4- methylpyridin-3- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2-methyl-4- (trifluoromethyl)pyridin-3-yl)methyl)-2-((3-methyl-8- (methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((6-amino-4-cyano-2- methylpyridin-3- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-4-methyl-2- (trifluoromethyl)pyridin-3-yl)methyl)-2-((3-methyl-8- (methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2-cyano-4- methylpyridin-3- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-fluoro-2- methylpyridin-3- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-chloro-2- methylpyridin-3- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-cyano-2- methylpyridin-3- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2-methyl-5- (trifluoromethyl)pyridin-3-yl)methyl)-2-((3-methyl-8- (methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((3-fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((3-fluoro-8-sulfamoylquinolin-6- yl)methyl)isonicotinamide

6-((4-(((1- aminoisoquinolin-6- yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3- fluoroquinoline-8- carboxylic acid

N-((3-chloro-1H- pyrrolo[2,3-b]pyridin-5- yl)methyl)-2-((3-fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H- indol-5-yl)methyl)-2-((3- fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2,4- dimethylpyridin-3- yl)methyl)-2-((3-fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((5-chloro-1H-indazol- 3-yl)methyl)-2-((3-fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2- methylpyridin-3- yl)methyl)-2-((3-fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-4- methylpyridin-3- yl)methyl)-2-((3-fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2-methyl-4- (trifluoromethyl)pyridin-3-yl)methyl)-2-((3-fluoro-8- (methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((6-amino-4-cyano-2- methylpyridin-3- yl)methyl)-2-((3-fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-4-methyl-2- (trifluoromethyl)pyridin-3-yl)methyl)-2-((3-fluoro-8- (methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2-cyano-4- methylpyridin-3- yl)methyl)-2-((3-fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-fluoro-2- methylpyridin-3- yl)methyl)-2-((3-fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-chloro-2- methylpyridin-3- yl)methyl)-2-((3-fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-cyano-2- methylpyridin-3- yl)methyl)-2-((3-fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2-methyl-5- (trifluoromethyl)pyridin-3-yl)methyl)-2-((3-fluoro-8- (methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-4-fluoro-1H- indol-5-yl)methyl)-2-((3- fluoro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2- methylpyridin-3- yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-4- methylpyridin-3- yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-1H- pyrrolo[2,3-b]pyridin-5- yl)methyl)-2-((3-methylquinolin-6- yl)methyl)isonicotinamide

N-((5-chloro-1H-indazol- 3-yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-4-fluoro-1H- indol-5-yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((6-fluoro-1H-indol-5- yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((6-fluoro-1H-indazol-5- yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((1H-pyrrolo[2,3- b]pyridin-5-yl)methyl)-2- ((3-methylquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-1H-indol-5- yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((5-chloro-1H-indol-3- yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-methyl-1H- indol-5-yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-methyl-1H- pyrrolo[2,3-b]pyridin-5- yl)methyl)-2-((3-methylquinolin-6- yl)methyl)isonicotinamide

N-((3-chloro-1H- pyrrolo[3,2-b]pyridin-5- yl)methyl)-2-((3-methylquinolin-6- yl)methyl)isonicotinamide

N-((1H-pyrrolo[3,2- b]pyridin-5-yl)methyl)-2- ((3-methylquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2- methylpyridin-3- yl)methyl)-2-((3- fluoroquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-4- methylpyridin-3- yl)methyl)-2-((3- fluoroquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2,4- dimethylpyridin-3- yl)methyl)-2-((3- fluoroquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-1H- pyrrolo[2,3-b]pyridin-5- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((5-chloro-1H-indazol- 3-yl)methyl)-2-((3- fluoroquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-4-fluoro-1H- indol-5-yl)methyl)-2-((3- fluoroquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-1H- pyrrolo[2,3-b]pyridin-5- yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((5-chloro-1H-indazol- 3-yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-fluoro-1H-indol-5- yl)methyl)-2-((3- fluoroquinolin-6-yl)methyl)isonicotinamide

N-((6-fluoro-1H-indazol-5- yl)methyl)-2-((3- fluoroquinolin-6-yl)methyl)isonicotinamide

N-((1H-pyrrolo[2,3- b]pyridin-5-yl)methyl)-2- ((3-fluoroquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-1H-indol-5- yl)methyl)-2-((3- fluoroquinolin-6-yl)methyl)isonicotinamide

N-((5-chloro-1H-indol-3- yl)methyl)-2-((3- fluoroquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-methyl-1H- indol-5-yl)methyl)-2-((3- fluoroquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-methyl-1H- pyrrolo[2,3-b]pyridin-5- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((3-chloro-1H- pyrrolo[3,2-b]pyridin-5- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((1H-pyrrolo[3,2- b]pyridin-5-yl)methyl)-2- ((3-fluoroquinolin-6-yl)methyl)isonicotinamide

N-((1H-benzo[d]imidazol- 5-yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((3-amino-1H-indazol- 6-yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((2- aminobenzo[d]oxazol-6- yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((2- aminobenzo[d]oxazol-5- yl)methyl)-2-((3- methylquinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)isoquinolin- 6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((3-methyl-8-sulfamoylisoquinolin-6- yl)methyl)isonicotinamide

6-((4-(((1- aminoisoquinolin-6- yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3- methylisoquinoline-8- carboxylic acid

N-((3-chloro-1H- pyrrolo[2,3-b]pyridin-5- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)isoquinolin- 6-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H- indol-5-yl)methyl)-2-((3- methyl-8-(methylsulfonyl)isoquinolin- 6-yl)methyl)isonicotinamide

N-((6-amino-2,4- dimethylpyridin-3- yl)methyl)-2-((3-methyl-8-(methylsulfonyl)isoquinolin- 6-yl)methyl)isonicotinamide

N-((5-chloro-1H-indazol- 3-yl)methyl)-2-((3-methyl- 8-(methylsulfonyl)isoquinolin-6- yl)methyl)isonicotinamide

N-((3-chloro-4-fluoro-1H- indol-5-yl)methyl)-2-((3- methyl-8-(methylsulfonyl)isoquinolin- 6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((2-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6- yl)methyl)-2-((2-methyl-8-sulfamoylquinolin-6- yl)methyl)isonicotinamide

6-((4-(((1- aminoisoquinolin-6- yl)methyl)carbamoyl)pyridin-2-yl)methyl)-2- methylquinoline-8- carboxylic acid

N-((3-chloro-1H- pyrrolo[2,3-b]pyridin-5- yl)methyl)-2-((2-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H- indol-5-yl)methyl)-2-((2- methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2,4- dimethylpyridin-3- yl)methyl)-2-((2-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((5-chloro-1H-indazol- 3-yl)methyl)-2-((2-methyl-8-(methylsulfonyl)quinolin- 6-yl)methyl)isonicotinamide

N-((3-chloro-4-fluoro-1H- indol-5-yl)methyl)-2-((2- methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide

N-((6-amino-4-cyano-2- methylpyridin-3- yl)methyl)-2-((3-methylquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2-methyl-4- (trifluoromethyl)pyridin-3- yl)methyl)-2-((3-methylquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-fluoro-2- methylpyridin-3- yl)methyl)-2-((3-methylquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-chloro-2- methylpyridin-3- yl)methyl)-2-((3-methylquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2-methyl-5- (trifluoromethyl)pyridin-3- yl)methyl)-2-((3-methylquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-cyano-2- methylpyridin-3- yl)methyl)-2-((3-methylquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2-cyano-4- methylpyridin-3- yl)methyl)-2-((3-methylquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-4-methyl-2- (trifluoromethyl)pyridin-3- yl)methyl)-2-((3-methylquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-4-cyano-2- methylpyridin-3- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2-methyl-4- (trifluoromethyl)pyridin-3- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-fluoro-2- methylpyridin-3- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-chloro-2- methylpyridin-3- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2-methyl-5- (trifluoromethyl)pyridin-3- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-5-cyano-2- methylpyridin-3- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-2-cyano-4- methylpyridin-3- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-4-methyl-2- (trifluoromethyl)pyridin-3- yl)methyl)-2-((3-fluoroquinolin-6- yl)methyl)isonicotinamide

N-((1-aminoimidazo[1,5- a]pyridin-6-yl)methyl)-2- ((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((8-aminoimidazo[1,5- a]pyrimidin-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((3-aminoimidazo[1,5- a]pyridin-7-yl)methyl)-2- ((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((6-aminoimidazo[1,5- a]pyrimidin-2-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((3-aminoimidazo[1,5- c]pyrimidin-7-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((7-aminoimidazo[1,5- b]pyridazin-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((1-amino-3- methylimidazo[1,5- a]pyridin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((8-amino-6- methylimidazo[1,5- a]pyrimidin-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((1-amino-3-methyl-2H- isoindol-5-yl)methyl)-2- ((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((3-amino-1- methylimidazo[1,5- a]pyridin-7-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((6-amino-8- methylimidazo[1,5- a]pyrimidin-2-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((3-amino-1- methylimidazo[1,5- c]pyrimidin-7-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((7-amino-5- methylimidazo[1,5- b]pyridazin-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((2-amino-3-methyl-1H- pyrrolo[2,3-b]pyridin-5- yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((2-amino-3-chloro-1H- pyrrolo[2,3-b]pyridin-5- yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((6-chloroimidazo[1,2- a]pyridin-3-yl)methyl)-2- ((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((3-chloropyrrolo[1,2- a]pyrimidin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((6-chloroimidazo[1,2- a]pyrimidin-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((6-chloro- [1,2,4]triazolo[4,3- a]pyridin-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((7-chloroimidazo[1,5- a]pyridin-1-yl)methyl)-2- ((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((5-chloro- [1,2,3]triazolo[1,5- a]pyridin-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((1-aminoimidazo[1,5- a]pyridin-6-yl)methyl)-2- ((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((3-aminoimidazo[1,5- a]pyridin-7-yl)methyl)-2- ((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((3-amino-1- methylimidazo[1,5- a]pyridin-7-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

N-((3-chloropyrrolo[1,2- a]pyrimidin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide

Preparation of Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants are optionally identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (contact theAmerican Chemical Society, Washington, D.C. for more details). Chemicalsthat are known but not commercially available in catalogs are optionallyprepared by custom chemical synthesis houses, where many of the standardchemical supply houses (e.g., those listed above) provide customsynthesis services. A reference for the preparation and selection ofpharmaceutical salts of the kallikrein inhibitory compound describedherein is P. H. Stahl & C. G. Wermuth “Handbook of PharmaceuticalSalts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical Compositions

In certain embodiments, the kallikrein inhibitory compound as describedherein is administered as a pure chemical. In other embodiments, thekallikrein inhibitory compound described herein is combined with apharmaceutically suitable or acceptable carrier (also referred to hereinas a pharmaceutically suitable (or acceptable) excipient,physiologically suitable (or acceptable) excipient, or physiologicallysuitable (or acceptable) carrier) selected on the basis of a chosenroute of administration and standard pharmaceutical practice asdescribed, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

Provided herein is a pharmaceutical composition comprising at least onekallikrein inhibitory compound, or a stereoisomer, pharmaceuticallyacceptable salt, hydrate, solvate, or N-oxide thereof, together with oneor more pharmaceutically acceptable carriers. The carrier(s) (orexcipient(s)) is acceptable or suitable if the carrier is compatiblewith the other ingredients of the composition and not deleterious to therecipient (i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient. One embodiment provides apharmaceutical composition comprising a compound of Formula (Ia), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In certain embodiments, the kallikrein inhibitory compound as describedby Formula (I) or (Ia) is substantially pure, in that it contains lessthan about 5%, or less than about 1%, or less than about 0.1%, of otherorganic small molecules, such as unreacted intermediates or synthesisby-products that are created, for example, in one or more of the stepsof a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract. Insome embodiments, suitable nontoxic solid carriers are used whichinclude, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,Remington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)).

The dose of the composition comprising at least one kallikreininhibitory compound as described herein differ, depending upon thepatient's (e.g., human) condition, that is, stage of the disease,general health status, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity. Optimal doses are generally determined usingexperimental models and/or clinical trials. The optimal dose dependsupon the body mass, weight, or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Kallikrein-Kinin System

Modulation of vascular permeability is important in regulating thepassage of small molecules or blood cells between blood vessels andsurrounding tissues. Vascular permeability depends upon thephysiological states of tissues such as during inflammation, changes inblood pressure, and fluctuations in ion and nutrient gradients. Thejunctions between the endothelial cells that line blood vessels are theimmediate controllers of vascular permeability. The strength of thesejunctions is tightly regulated by the kinin-kallikrein system ofpolypeptides and enzymes. Abnormalities in the kinin-kallikrein systemlead to a range of pathologies including angioedema, macular edema andbrain edema. Angioedema is a potentially fatal blood disordercharacterized by swelling that may occur in the face, gastrointestinaltract, extremities, genitals and upper airways. Genetic hereditaryangioedema attacks result from the unregulated activation of thekallikrein system with uncontrolled increases in vascular permeability.Currently there is a need for agents that are useful for the treatmentof angioedema and for agents that inhibit plasma kallikrein.

The kallikrein-kinin system represents a metabolic cascade that, whenactivated, triggers the release of vasoactive kinins. Thekinin-kallikrein system (KKS) consists of serine proteases involved inthe production of kinins, principally bradykinin and Lys-bradykinin(kallidin). The KKS contributes to a variety of physiological processesincluding inflammation, blood pressure control and coagulation. Theactivation of this system is particularly important in blood pressureregulation and in inflammatory reactions, due to the ability ofbradykinin to elevate vascular permeability and to cause vasodilatationof arteries and veins of the gut, aorta, uterus and urethra. Thekinin-kallikrein system, also referred to as the contact system,consists of three serine proenzymes (factor XII (FXII) or Hagemanfactor, factor IX (FIX), and prekallikrein), and the kinin precursorhigh molecular weight kinin (HK). Contact activation is triggered by thebinding of FXII to a negatively charged surface and involves theformation of α-FXIIa via autocatalysis. Bound α-FXIIa convertsprekallikrein into kallikrein. Kallikrein can further convert α-FXIIa toβ-FXIIa by an additional cleavage at R334-N335, a positive feedbackmechanism that leads to sufficient kallikrein production to drivedownstream processes. α-FXIIa consists of a heavy and light chain thatare disulphide linked, whereas β-FXIIa lacks the heavy chain and losesits capacity to bind to negatively charged surfaces (Stavrou E, SchmaierA H., Thrombosis Research, 2010, 125(3) pp. 210-215). The N-terminalregion of FXII (α-FXIIa heavy chain) shows strong homology withtissue-type plasminogen activator (tPA), with the presence offibronectin type I, epidermal growth factor, and Kringle domains (Ny etal., Proc Natl Acad Sci USA, 1984, 81(17) pp. 5355-5359; Cool D E,MacGillivray R T, The Journal of Biological Chemistry, 1987, 262(28) pp.13662-13673). Kallikrein is a trypsin-like serine protease enzyme thatcleaves high molecular weight kinin (HK) to produce bradykinin.Bradykinin then binds to the bradykinin 2R receptors (BK2R) onendothelial cells to trigger an increase in vascular permeability.

Protease inhibitors regulate the activation of the contact system.Several known serpins of plasma are C1-inhibitor (C1INH), antithrombinIII, α2-macroglobulin, α1-protease inhibitor, and α2-antiplasmin (Kaplanet al., Advances in Immunology, 1997 (66) pp. 225-72; Pixley et al., TheJournal of Biological Chemistry, 1985, 260(3) pp. 1723-9). However,C1INH is the major regulator of the intrinsic system, interfering withthe activities of factor XIIa and of kallikrein (Cugno et al., TheJournal of Laboratory and Clinical Medicine, 1993, 121(1) pp. 38-43).Both C1INH and α2-macroglobulin account for more than 90% of thekallikrein inhibitory activity of plasma. Thus, the FXII-dependentkallikrein-kinin system is tightly regulated by the CINH and whenregulation of the FXII-dependent kallikrein-kinin system fails, in asubject, the subject is believed to suffer from hereditary angioedema(HAE) that is characterized by invalidating edema attacks.

Angioedema is a potentially fatal blood disorder characterized byswelling that may occur in the face, gastrointestinal tract,extremities, genitals and upper airways. Angioedema attacks begin in thedeeper layers of the skin and mucous membranes with localized bloodvessel dilatation and increased permeability. Symptoms of the diseaseresult from the leakage of plasma from blood vessels into surroundingtissues. Genetic hereditary angioedema attacks result from unregulatedactivation of the kallikrein system with consequent overproduction ofbradykinin and uncontrolled increases in vascular permeability. Asvascular permeability rises beyond normal, plasma leaks out of thevasculature into surrounding tissue, causing swelling (Mehta D and MalikA B, Physiol. Rev., 86 (1), 279-367, 2006; Sandoval R et al., J.Physiol., 533(pt 2), 433-45, 2001; Kaplan A P and Greaves M W,Angioedema. J. Am. Acad. Dermatol., 2005).

HAE results from mutations in the genes that code for elements of thecoagulation and inflammation pathways. The three forms of HAE aredistinguished by their underlying causes and levels of the C1-esteraseinhibitor (C1INH, serpin peptidase inhibitor, Glade G, member 1) proteinin the blood, which inhibits the activity of plasma kallikrein. In typeI, patients have insufficient levels of functional C1INH, while type IIpatients have dysfunctional C1INH. While type I and II affect men andwomen at equal rates, type III, which primarily affects women, resultsfrom a mutation in coagulation factor XII (Hageman factor; HAE-FXII).The underlying causes of type I and II HAE are autosomal dominantmutations in C1INH gene (SERPING1 gene) on chromosome 11 (11q12-q13.1).

C1INH accounts for 90% of inhibition of FXIIa and 50% of inhibition ofplasma kallikrein (Pixley R A et al., J. Biol. Chem., 260, 1723-9, 1985;Schapira M et al., Biochemistry, 20, 2738-43, 1981). In addition, C1INHalso inactivates prekallikrein (Colman R W et al, Blood, 65, 311-8,1985). When C1INH levels are normal, its activity blocks FXIIa fromconverting prekallikrein to kallikrein and blocks kallikrein'sconversion to HK, thus preventing the production of bradykinin and theedemic episodes. When C1INH levels are low, or levels of dysfunctionalC1INH are high, this inhibition fails and the pathogenic process ensues.

In addition to HAE, plasma kallikrein also contributes to non-hereditaryangioedema, high altitude cerebral edema, cytotoxic cerebral edema,osmotic cerebral edema, diabetic macular edema (DME), clinicallysignificant macular edema, cystoid macular edema (CME, Gao B B, NatMed., 13(2), 181-8, 2007), retinal edema, radiation induced edema, lymphedema, glioma-associated edema, allergic edema e.g. airflow obstructionin chronic allergic sinusitis or perennial rhinitis. Other disorders ofthe plasma kallikrein system include retinopathy and diabeticretinopathy (Liu J and Feener E P, Biol. Chem. 394(3), 319-28, 2013),proliferative and non-proliferative retinopathy (Liu J et al, Invest.Ophthalmol. Vis. Sci., 54(2), 2013), CME following cataract extraction,CME induced by cryotherapy, CME induced by uveitis, CME followingvascular occlusion (e.g., central retinal vein occlusion, branch retinalvein occlusion or hemiretinal vein occlusion), complications related tocataract surgery in diabetic retinopathy, hypertensive retinopathy (JAPhillips et al., Hypertension, 53, 175-181, 2009), retinal trauma, dryand wet age-related macular degeneration (AMD), ischemic reperfusioninjuries (C Storoni et al., JPET, 381, 849-954, 2006), e.g., in avariety of contexts associated with tissue and/or organ transplantation.

Current treatments for angioedema, and those under development, targetdifferent elements in the HAE pathway. Three classes of therapies arecurrently available: (a) replacement therapy with C1INH concentrates(e.g., Cinryze, Berinert), (b) administration of selective kallikreininhibitors (e.g., Ecallantide) and (c) bradykinin receptors antagonists(e.g., Firazyr).

Replacement therapies have proven useful for both acute attacks,including emergency situations, such as laryngeal edema (Bork K et al.,Transfusion, 45, 1774-1784, 2005; Bork K and Barnstedt S E, Arch.Intern. Med., 161, 714-718, 2001) and prophylaxis. Selective C1INHinhibitors inactivate both α-FXIIa and β-FXIIa molecules active early inthe HAE pathway that catalyze the production of kallikrein (Muller F andRenne T, Curr. Opin. Hematol., 15, 516-21, 2008; Cugno M et al., TrendsMol. Med. 15(2):69-78, 2009). In addition to HAE, plasma kallikreininhibitors are considered to be useful in the treatment of other edemassuch as macular edema and brain edema, and retinopathy, e.g.,retinopathy associated with diabetes and/or hypertension. There isevidence that plasma kallikrein inhibitors are also also effective inthe treatment of edema formation in diseases, e.g., edema formationrelated to ischemic reperfusion injuries. The bradykinin receptorsantagonists prevent bradykinin from activating the vascular permeabilitypathway and stop the initiation of swelling.

Methods of Treatment

Disclosed herein are methods of treating diseases or disorders whereinthe inhibition of plasma kallikrein is indicated. Such diseases anddisorders include but are not limited to angioedema, includinghereditary and non-hereditary.

In some embodiments, the methods disclosed herein are useful for thetreatment of angioedema. In some embodiments, the angioedema ishereditary angioedema (HAE). One embodiment provides a method oftreating angioedema in a patient in need thereof comprisingadministration of a composition comprising a compound of Formula (I), ora pharmaceutically acceptable salt thereof. Another embodiment providesthe method wherein the angioedema is hereditary angioedema.

One embodiment provides a method of treating angioedema in a patient inneed thereof comprising administration of a composition comprising acompound of Formula (Ia), or a pharmaceutically acceptable salt thereof.Another embodiment provides the method wherein the angioedema ishereditary angioedema.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

EXAMPLES I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants, J are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

The following abbreviations and terms have the indicated meaningsthroughout:

-   AcOH=acetic acid-   B₂pin₂=bis(pinacolato)diboron-   Boc=tert-butoxycarbonyl-   DCC=dicyclohexylcarbodiimide-   DIEA=N,N-diisopropylethylamine-   DMAP=4-dimethylaminopyridine-   EDC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-   eq=equivalent(s)-   Et=ethyl-   EtOAc or EA=ethyl acetate-   EtOH=ethanol-   g=gram-   h or hr=hour-   HBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt=hydroxybenzotriazole-   HPLC=high pressure liquid chromatography-   kg or Kg=kilogram-   L or 1=liter-   LC/MS=LCMS=liquid chromatography-mass spectrometry-   LRMS=low resolution mass spectrometry-   m/z=mass-to-charge ratio-   Me=methyl-   MeOH=methanol-   mg=milligram-   min=minute-   mL=milliliter-   mmol=millimole-   NaOAc=sodium acetate-   PE=petroleum ether-   Ph=phenyl-   Prep=preparative-   quant.=quantitative-   RP-HPLC=reverse phase-high pressure liquid chromatography-   rt or RT=room temperature-   THF=tetrahydrofuran-   UV=ultraviolet

Intermediate 1: Preparation of2-((2-cyanoquinolin-6-yl)methyl)isonicotinic acid

Step 1: Preparation of 6-methylquinoline 1-oxide

To a solution of 6-methylquinoline (10.0 g, 69.9 mmol, 1.0 eq) in HOAc(150 mL) was added 30% H₂O₂ (100 mL), The reaction mixture was heated to70° C. and stirred overnight, then cooled, and water (100 mL) was added,then Na₂SO₃ was added portion wise to quench excess H₂O₂ while coolingin ice bath. The reaction mixture was extracted with DCM and the organicphase was washed with water, brine, dried over anhydrous sodium sulfate,filtered and concentrated to dryness to afford 6-methylquinoline 1-oxideas a brown oil (7.2 g, 64%).

Step 2: Preparation of 6-methylquinoline-2-carbonitrile

To a solution of 6-methylquinoline 1-oxide (7.2 g, 45.2 mmol, 1.0 eq) intrimethylsilycyanide (17.0 mL, 135.8 mmol, 3.0 eq) was added benzoylchloride (15.6 mL, 135.8 mmol, 3.0 eq) while cooling in ice-water bathfollowed by triethylamine (18.9 mL, 135.8 mmol, 3.0 eq). The reactionwas stirred for 1 h. The mixture was diluted with DCM, washed once withsaturated aqueous NaHCO₃ carefully, then washed with water, brine, driedover anhydrous sodium sulfate, and purified on silica gel column(PE/DCM/EtOAc=10/1/1) and then triturated from EtOH to afford6-methylquinoline-2-carbonitrile as a yellow solid (6.0 g, 78%).

Step 3: Preparation of 6-(bromomethyl)quinoline-2-carbonitrile

The mixture of 6-methylquinoline-2-carbonitrile (3.7 g, 22.0 mmol, 1.0eq), NBS (3.9 g, 22.0 mmol, 1.0 eq) and AIBN (72 mg, 2 mol %) intetrachloride carbon (100 mL) was refluxed for 3 h, then cooled andconcentrated to dryness. The residue was triturated from DCM, filteredand dried to afford 6-(bromomethyl)quinoline-2-carbonitrile as a whitesolid (4.0 g, 74%).

Step 4: Preparation of ethyl2-((2-cyanoquinolin-6-yl)methyl)isonicotinate

The mixture of ethyl 2-bromoisonicotinate (1.86 g, 8.1 mmol, 1.0 eq),BPDB (2.06 g, 8.1 mmol, 1.0 eq), potassium acetate (2.38 g, 24.3 mmol,3.0 eq) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(296 mg, 5 mol %) were mixed in 1,4-dioxane (100 mL). The mixture wasdegassed with nitrogen, heated to 85° C. and stirred for 16 h, thencooled to rt, and 6-(bromomethyl)quinoline-2-carbonitrile (2.0 g, 8.1mmol, 1.0 eq),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (296 mg, 5mol %) and sodium carbonate (2.57 g, 24.3 mmol, 3.0 eq, dissolved in 30mL of water) were added. The mixture was degassed, heated to 95° C. andstirred overnight. The mixture was cooled and filtered through celite.Water (100 mL) and DCM (100 mL) were added to the filtrate. The DCMlayer was separated and washed with brine, dried over anhydrous sodiumsulfate, and purified on silica gel column to afford ethyl2-((2-cyanoquinolin-6-yl)methyl)isonicotinate as a red solid (670 mg,26%).

Step 5: Preparation of 2-((2-cyanoquinolin-6-yl)methyl)isonicotinic acid

To the solution of ethyl 2-((2-cyanoquinolin-6-yl)methyl)isonicotinate(670 mg, 2.1 mmol, 1.0 eq) in THF (6 mL) was added an aqueous solutionof lithium hydroxide monohydrate (177 mg, 4.2 mmol, 2.0 eq) in water (3mL). The reaction was stirred for 2 h, then acidified with 2N HCl to pH3. DCM (50 mL) and water (50 mL) were added, and the DCM layer wasseparated and washed with brine, dried over anhydrous sodium sulfate,and purified via flash chromatography to afford2-((2-cyanoquinolin-6-yl)methyl)isonicotinic acid as a brown solid (250mg, 80% purity).

Intermediate 2: Preparation of2-((3-chloroquinolin-6-yl)methyl)isonicotinic acid

Step 1: Preparation of methyl 3-chloroquinoline-6-carboxylate

To a solution of methyl quinoline-6-carboxylate (15.0 g, 80.2 mmol, 1.0eq) in DMF (200 ml) was added N-chlorosuccinimide (21.4 g, 0.16 mol, 2.0eq) and the reaction mixture was stirred at 120° C. for 20 h. Thereaction mixture was allowed to cool to rt, treated with brine and themixture was extracted with ethyl acetate. The organic layer was driedover Na₂SO₄, filtered and concentrated under vacuum. The crude productwas purified by chromatography on silica gel (EtOAc/PE=1/8, v/v) toafford methyl 3-chloroquinoline-6-carboxylate (9.1 g, 51%) as a yellowsolid.

Step 2: Preparation of methyl (3-chloro-quinolin-6-yl)-methanol

To a solution of methyl 3-chloroquinoline-6-carboxylate (8 g, 36.0 mmol,1.0 eq) in dry THF was added LiAlH₄ (2.5M in THF, 5.8 mL, 0.4 eq). Theresulting mixture was stirred at 0° C. for 1 h. After which period,additional LiAlH₄ (2.5M in THF, 2.8 mL, 0.2 eq) was added. The systemwas stirred for another 30 min at 0° C. and quenched by the slowaddition of 1N aqueous NaOH. The resulting precipitate was filtered, andthe filtrate was extracted with ethyl acetate. The combined organiclayers were dried and concentrated. The residue was purified by silicagel chromatography (PE/EtOAc=20/1˜5/1, v/v) to afford(3-chloro-quinolin-6-yl)-methanol (4.8 g, 69%) as a white solid.

Step 3: Preparation of 3-chloro-6-chloromethyl-quinoline

To (3-chloro-quinolin-6-yl)-methanol (3.3 g, 17.1 mmol, 1.0 eq) wasadded SOCl₂ (50 mL) and the mixture was stirred at rt for 1 h. Thevolatiles were then removed under vacuum and the residue was dissolvedin DCM. The mixture was washed with saturated aq. NaHCO₃, dried andconcentrated to give 3-chloro-6-chloromethyl-quinoline (3.4 g, 94%) as ayellow solid.

Step 4: Preparation of methyl 2-(trimethylstannyl)isonicotinate

Hexamethyldistannane (0.21 mL, 334 mg, 1.02 mmol) andtetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) were addedto a solution of methyl 2-chloroisonicotinate (100 mg, 0.58 mmol) in drydioxane (10 mL) and the resulting mixture was refluxed for 3 h under N₂.EtOAc (50 mL) and water (100 mL) were then added. The layers wereseparated and the organic layer was washed with water (5×100 mL), dried(Na₂SO₄), and the solvent removed by rotary evaporation to leave cruderesidue which was used in the next step without further purification.

Step 4: Preparation of methyl2-((3-chloroquinolin-6-yl)methyl)isonicotinate

To a solution of 3-chloro-6-chloromethyl-quinoline (110 mg, 0.52 mmol,1.0 eq) and crude methyl 2-(trimethylstannyl)isonicotinate in dioxane(10 mL) Pd(PPh₃)₂Cl₂ (36 mg, 0.05 mmol, 0.1 eq). The mixture was stirredat 90° C. for 3 h under nitrogen atmosphere, stripped of solvent andpurified by silica gel chromatography (EtOAc/PE=10/1˜5:1, v/v) to affordmethyl 2-((3-chloroquinolin-6-yl)methyl)isonicotinate (70 mg) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (m, 2H), 8.53 (d, 1H),7.98 (d, 1H), 7.85 (d, 1H), 7.73 (dd, 1H), 7.58 (s, 1H), 7.57 (s, 1H),4.36 (s, 2H), 3.85 (s, 3H).

Step 5: Preparation of 2-((3-chloroquinolin-6-yl)methyl)isonicotinicacid

To a solution of methyl 2-((3-chloroquinolin-6-yl)methyl)isonicotinate(70 mg, 0.22 mmol, 1.0 eq.) in THF/H₂O (5 mL/1 mL) was added LiOH (71mg, 2.1 mmol, 10 eq.). The resulting mixture was stirred for 1 h at roomtemperature; all starting material had been consumed (assessed by TLC).Volatile solvent was removed on rotavap, the aqueous residue wasneutralized with 1M HCl and extracted with EtOAc (10 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated to furnish crude acid (50 mg, 75%), which was used directlywithout further purification.

Intermediate 3: Preparation of2-((3-chloro-8-fluoroquinolin-6-yl)methyl)isonicotinic acid

Step 1: Preparation of methyl 8-fluoroquinoline-6-carboxylate

A mixture of methyl 4-amino-3-fluorobenzoate (35 g, 0.207 mmol, 1 eq),acrolein (17.4 g, 0.311 mol, 1.5 eq) and 6N HCl (600 mL) was stirred at100° C. for 10 min. Then the mixture was cooled and adjusted to pH˜5-6using NaHCO₃ (aq). The mixture was extracted with DCM. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered thenconcentrated and purified by column chromatography (EtOAc/PE=1/20, v/v)to give methyl 8-fluoroquinoline-6-carboxylate (11 g, 21%) as a yellowsolid.

Step 2: Preparation of methyl 3-chloro-8-fluoroquinoline-6-carboxylate

To a solution of methyl 8-fluoroquinoline-6-carboxylate (11 g, 53.7mmol, 1 eq) in DMF was added NCS (21.4 g, 0.161 mol, 3 eq). The reactionmixture was stirred at 120° C. overnight. The reaction mixture wasallowed to cool to ambient temperature, treated with water, neutralizedwith solid NaHCO₃ and further stirred at rt for 30 min. Finally,powdered sodium thiosulfate was carefully added to remove excess of NCS.The mixture was extracted with ethyl acetate. The organic layer wasdried and concentrated under vacuum. The crude product was purified byflash-chromatography on silica gel to afford methyl3-chloro-8-fluoroquinoline-6-carboxylate (11.5 g, 90%) as a yellowsolid.

Step 3: Preparation of (3-chloro-8-fluoro-quinolin-6-yl)-methanol

To a solution of methyl 3-chloro-8-fluoroquinoline-6-carboxylate (4.5 g,18.8 mmol, 1 eq) was added LiAlH(t-BuO)₃ (12.0 g, 47.1 mmol, 2.5 eq).The resulting mixture was stirred at 40° C. for 12 h and then quenchedby the addition of water. The mixture was extracted with ethyl acetate.The combined extracts were dried and concentrated. The residue waspurified by silica gel chromatography (PE/EtOAc=2/1, v/v) to afford(3-chloro-8-fluoro-quinolin-6-yl)-methanol (2.1 g, 53%) as a yellowsolid.

Step 4: Preparation of 3-chloro-6-chloromethyl-8-fluoro-quinoline

A mixture of 3-chloro-8-fluoro-6-hydroxymethyl-quinoline (2.1 g, 9.95mmol, 1.0 eq) in SOCl₂ (50 mL) was stirred at rt for 1 h andconcentrated. The residue was dissolved in DCM and treated withsat.NaHCO₃ solution to give 3-chloro-6-chloromethyl-8-fluoro-quinoline(2.2 g, 96%) as a yellow solid.

Step 5: Preparation of methyl2-((3-chloro-8-fluoroquinolin-6-yl)methyl)isonicotinate

To a solution of 3-chloro-6-chloromethyl-8-fluoro-quinoline (2.2 g, 9.61mmol, 1.0 eq) in dioxane (60 mL) was added methyl2-(trimethylstannyl)isonicotinate (3.18 g, 10.6 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (674 mg, 0.96 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, concentrated and purified bysilica gel chromatography (DCM/MeOH=200/1, v/v) to afford methyl2-((3-chloro-8-fluoroquinolin-6-yl)methyl)isonicotinate (1.6 g, 50%) asa yellow solid.

Step 6: Preparation of2-((3-chloro-8-fluoroquinolin-6-yl)methyl)isonicotinic acid

To a solution of methyl2-((3-chloro-8-fluoroquinolin-6-yl)methyl)isonicotinate (800 mg, 2.4mmol, 1 eq) in THF (20 ml)/water (10 ml) was added NaOH (116 mg, 0.29mmol, 1.2 eq). The mixture was stirred at rt for 3 h. Then aqueous HCl(2N) was added to the reaction mixture until pH 6-7. The mixture wasextracted with ethyl acetate, and the organic layer was concentratedunder pressure. The gray compound was directly used in next step (500mg, 76%).

Intermediate 4: Preparation of2-((3,8-dichloroquinolin-6-yl)methyl)isonicotinic acid

The title compound was synthesized as described for Intermediate 3 usingmethyl 4-amino-3-chlorobenzoate as a starting material.

Intermediate 5: Preparation of2-((4-cyanoquinolin-6-yl)methyl)isonicotinic acid

Step 1: Preparation of 6-(methoxycarbonyl)quinoline 1-oxide

A mixture of methyl quinoline-6-carboxylate (10 g, 53.5 mmol, 1 eq) andm-CPBA (18.4 g, 0.106 mol, 2 eq) in DCM (50 mL) was stirred at rtovernight. Saturated aq. NaHCO₃ (40 mL) was added to the reactionmixture and it was stirred for 30 min. The organic layer was separated,dried, filtered and concentrated to obtain a residue, which wasre-crystallized by ethyl acetate (5 mL) to afford6-(methoxycarbonyl)quinoline 1-oxide (8.0 g, 74%) as a light yellowsolid.

Step 2: Preparation of methyl 2-chloroquinoline-6-carboxylate and methyl4-chloroquinoline-6-carboxylate

To 6-(methoxycarbonyl)quinoline 1-oxide (4.0 g, 19.7 mmol, 1 eq) wasadded phosphoryl trichloride (20 mL). The resulting mixture was thenstirred at rt under N₂ for 2 h. The volatiles were then removed undervacuum and the residue was dissolved in DCM. The mixture was washed withsaturated aq. NaHCO₃, dried and concentrated. The residue was purifiedby silica gel chromatography (PE/EtOAc=10/1, v/v) to afford methyl2-chloroquinoline-6-carboxylate (1.2 g, 28%) and methyl4-chloroquinoline-6-carboxylate (2.5 g, 57%).

Step 3: Preparation of (4-chloro-quinolin-6-yl)-methanol

To a solution of methyl 4-chloroquinoline-6-carboxylate (2.2 g, 10 mmol,1 eq) was added LiAlH(t-BuO)₃ (7.62 g, 30 mmol, 3 eq). The resultingmixture was stirred at 60° C. for 2 h and then quenched by the additionof water. The mixture was extracted with EtOAc. The combined extractswere dried and concentrated. The residue was purified by silica gelchromatography (PE/EtOAc=1/1, v/v) to afford(4-chloro-quinolin-6-yl)-methanol (1.54 g, 80%) as a yellow solid.

Step 4: Preparation of 6-hydroxymethyl-quinoline-4-carbonitrile

To a mixture of (4-chloroquinolin-6-yl)methanol and zinc cyanide in DMF(30 mL) was added palladium tetrakis(triphenylphosphine). The mixturewas degassed and then heated to 90° C. for 3 h. After this time, themixture was diluted with water and EtOAc, filtered and the resultinglayers were separated. The aqueous layer was further extracted withEtOAc. The combined extracts were washed with water, dried over MgSO₄,filtered and the solvent removed in vacuo. The resulting residue waspurified by chromatograph on silica gel column to afford6-hydroxymethyl-quinoline-4-carbonitrile as an off-white solid (1.1 g,77%).

Step 5: Preparation of 2-((4-cyanoquinolin-6-yl)methyl)isonicotinic acid

The title compound was synthesized as described for Intermediate 3,Steps 4, 5 and 6.

Intermediate 6: Preparation of2-((7-chloroquinolin-3-yl)methyl)isonicotinic acid

Step 1: Preparation ofN′-(7-chloroquinoline-3-carbonyl)-4-methylbenzenesulfonohydrazide

To a solution of ethyl 7-chloroquinoline-3-carboxylate (3.5 g, 14.90mmol, 1.0 eq) in EtOH (60 mL) was added hydrazine monohydrate (7.2 mL,149 mmol, 10 eq). The reaction mixture was stirred at 80° C. for 2 h,and then concentrated under reduced pressure. Water was added to thereaction flask and the solid was filtered and washed with cold water.The solid was dried in air and then dissolved in pyridine (30 mL). Tothe mixture was added TsCl (3.4 g, 17.90 mmol, 1.2 eq). After stirringat rt for 1 h, the mixture was concentrated in vacuo. The residue waspoured into water and the resulting precipitate was collected byfiltration to giveN′-(7-chloroquinoline-3-carbonyl)-4-methylbenzenesulfonohydrazide (5.0g, 90%) as a yellow solid.

Step 2: Preparation of (7-chloro-quinolin-3-yl)-methanol

A mixture ofN′-(7-chloroquinoline-3-carbonyl)-4-methylbenzenesulfonohydrazide (5.0g, 13.30 mmol, 1.0 eq) and Na₂CO₃ (4.24 g, 40 mmol, 3 eq) in ethyleneglycol (30 mL) was heated at 160° C. for 20 min. After cooling to rt themixture was diluted with water and extracted with Et₂O. The combinedextracts were dried and concentrated. The residue was purified by flashchromatography on a silica gel column (PE/EtOAc=1/1, v/v) to give(7-chloro-quinolin-3-yl)-methanol (600 mg, 23%) as a yellow solid.

Step 3: Preparation of 2-((7-chloroquinolin-3-yl)methyl)isonicotinicacid

The title compound was synthesized as described for Intermediate 3,Steps 4, 5 and 6.

Intermediate 7: Preparation of2-((3-methylisoquinolin-6-yl)methyl)isonicotinic acid

Step 1: Preparation of 6-bromo-3-methyl-isoquinoline

To a solution of 4-bromo-benzylamine (10.0 g, 54 mmol, 1.0 eq) in DCE(100 mL) was added 1,1-dimethoxy-propan-2-one (7.0 g, 59 mmol, 1.1 eq)and MgSO₄ (20 g). The mixture was stirred at 40° C. overnight. Then tothe mixture was added NaBH₃CN (4.08 g, 64.8 mmol, 1.2 eq). Afterstirring at rt for 5 h the mixture was filtered. The filtrate wasconcentrated to give a yellow oil. Chlorosulfonic acid (30 mL) wascooled to −10° C. and the above crude product was added dropwise. Thereaction mixture was heated to 100° C. for 10 min, then cooled andpoured into ice. The mixture was neutralized with 2M NaOH and extractedwith ethyl acetate. The combined extracts were dried and concentrated.The residue was purified by silica gel chromatography (PE/EtOAc=2/1,v/v) to afford 6-bromo-3-methyl-isoquinoline (4.0 g, 34% yield for 3steps) as a yellow solid.

Step 2: Preparation of methyl 3-methylisoquinoline-6-carboxylate

An autoclave vessel was charged with 6-bromo-3-methyl-isoquinoline (4.0g, 18 mmol), Pd(dppf)Cl₂ (735 mg, 0.9 mmol, 0.05 eq) and triethylamine(5.0 mL, 36 mmol, 2 eq) in 40 mL of methanol. The vessel was purged withnitrogen three times and carbon monoxide three times. The vessel waspressurized to 3 MPa with carbon monoxide and heated to 100° C. Thereaction was thus stirred overnight, then allowed to cool to roomtemperature. The resulting solution was concentrated and purified byflash chromatography on silica gel (PE/EtOAc=1/1, v/v) to afford methyl3-methylisoquinoline-6-carboxylate (3.4 g, 94%) as a white solid.

Step 3: Preparation of (3-methyl-isoquinolin-6-yl)-methanol

To a solution of methyl 3-methylisoquinoline-6-carboxylate (3.3 g, 16.42mmol, 1 eq) in dry THF (100 mL) was added LiAlH(t-BuO)₃ (12.5 g, 45.25mmol, 3 eq). The resulting mixture was stirred at 60° C. for 5 h andthen quenched by the addition of water. The mixture was extracted withethyl acetate. The combined extracts were dried and concentrated. Theresidue was purified by silica gel chromatography (PE/EtOAc=1/1, v/v) toafford (3-methyl-isoquinolin-6-yl)-methanol (2.5 g, 89%) as a whitesolid.

Step 4: Preparation of 2-((3-methylisoquinolin-6-yl)methyl)isonicotinicacid

The title compound was synthesized as described for Intermediate 3,Steps 4, 5 and 6.

Intermediates 8-14

The title compounds were synthesized as described for Intermediate 7.

Inter- mediate Structure Name 8

2-(quinolin-6- ylmethyl)isonicotinic acid 9

2-((3-methylquinolin-6- yl)methyl)isonicotinic acid 10

2-((2-methylquinolin-6- yl)methyl)isonicotinic acid 11

2-((6-methylquinolin-3- yl)methyl)isonicotinic acid 12

2-((2-methylquinolin-7- yl)methyl)isonicotinic acid 13

2-((6-fluoroquinolin-3- yl)methyl)isonicotinic acid 14

2-((7-fluoroquinolin-3- yl)methyl)isonicotinic acid

Intermediate 15: Preparation of5-(aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride

Step 1: Preparation of 5-iodo-4,6-dimethyl-pyridin-2-ylamine

A mixture of 4,6-dimethyl-pyridin-2-ylamine (6 g, 49.1 mmol, 1.0 eq),periodic acid (1.6 g, 7.37 mmol, 0.15 eq) and iodine (6.2 g, 24.5 mmol,0.5 eq) was added in a mixed solution of acetic acid (120 mL), H₂O₂ (6mL) and H₂SO₄ (1 mL) at 80° C. for 4 h, then reaction mixture was pouredinto 10% aqueous Na₂S₂O₃ solution to quench any unrecalled iodine andextracted with ether. The extract was washed with 10% aqueous NaOH,dried over Na₂SO₄ and concentrated, the resulting residue was purifiedby silica gel chromatography (DCM/MeOH=100/1, v/v) to afford5-iodo-4,6-dimethyl-pyridin-2-ylamine (10 g, 80%) as a yellow solid.

Step 2: Preparation of 6-amino-2,4-dimethyl-nicotinonitrile

To a solution of 5-iodo-4,6-dimethyl-pyridin-2-ylamine (10 g, 40.3 mmol,1.0 eq) in DMF (300 mL) was added Zn(CN)₂ (14 g, 120.9 mmol, 3.0 eq) andPd(PPh₃)₄ (4.65 g, 4.03 mmol, 0.1 eq) carefully. The mixture was stirredat 90° C. overnight under N₂. ethyl acetate and water was added. Theorganic layer was separated and concentrated. The resulting residue waspurified by silica gel chromatography (DCM/MeOH=100/1, v/v) to afford6-amino-2,4-dimethyl-nicotinonitrile (5 g, 84%) as a yellow solid.

Step 3: Preparation of tert-butyl(6-amino-2,4-dimethylpyridin-3-yl)methylcarbamate

To a solution of 6-amino-2,4-dimethyl-nicotinonitrile (8.1 g, 55 mmol,1.0 eq) in THF (300 mL) was added BH₃.MeS₂ (10M, 55 mL, 550 mmol, 10.0eq) at rt slowly. The mixture was stirred under reflux for 48 h. Aftercooling to rt, the mixture was quenched by the addition of concentratedHCl. The mixture was basified to pH 8 with sat. NaHCO₃ solution. To themixture were added TEA (9.2 mL, 66 mmol, 1.2 eq) and Boc₂O (14.4 g, 66mmol, 1.2 eq). The reaction mixture was stirred at rt for 1 h and thenextracted with ethyl acetate. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The residue was purified onsilica gel column (PE/EtOAc=1/1) to give tert-butyl(6-amino-2,4-dimethylpyridin-3-yl)methylcarbamate (4.1 g, 30%) as ayellow solid.

Step 4: Preparation of 5-aminomethyl-4,6-dimethyl-pyridin-2-ylaminehydrochloride

To a solution of tert-butyl(6-amino-2,4-dimethylpyridin-3-yl)methylcarbamate (4.1 g, 16.3 mmol, 1.0eq) in ethyl acetate (20 mL) was added a solution of HCl in ethylacetate (10M, 50 mL). The mixture was stirred at rt for 1 h, and theprecipitate was collected by filtration to afford5-aminomethyl-4,6-dimethyl-pyridin-2-ylamine hydrochloride (2.0 g, 66%)as a white solid.

Intermediate 16: Preparation of 6-(aminomethyl)isoquinolin-1-amine

Step 1: Preparation of 6-bromo-1-chloroisoquinoline

To a solution of 6-bromoisoquinolin-1-ol (10 g, 44.4 mmol, 1.0 eq) inPOCl₃ (200 mL). The mixture was stirred at 120° C. for overnight. Themixture was concentrated and extracted with DCM and the combinedextracts were washed with brine, dried and concentrated to give6-bromo-1-chloroisoquinoline as a yellow solid (10 g, crude).

Step 2: Preparation of 6-bromoisoquinolin-1-amine

To a solution of 6-bromo-1-chloroisoquinoline (10 g, 41.50 mmol, 1.0 eq)in MeOH/NH₃ (500 mL) and was stirred at 30° C. for 48 h. The mixture wasconcentrated to give 6-bromoisoquinolin-1-amine as a yellow solid (10 g,crude).

Step 3: Preparation of 1-aminoisoquinoline-6-carbonitrile

To a solution of 6-bromoisoquinolin-1-amine (10 g, 45.04 mmol, 1.0 eq)in DMF (400 mL) was added Zn(CN)₂ (13.22 g, 112.3 mmol, 2.5 eq) andPd(pph₃)₄ (5.2 g, 4.51 mmol, 0.1 eq). The mixture was stirred at 120° C.for 4 h. The mixture was concentrated and extracted with DCM. Thecombined extracts were dried and concentrated. The residue was purifiedby flash chromatography on a silica gel column (DCM/MeOH=50/1, v/v) togive 1-aminoisoquinoline-6-carbonitrile (4.5 g, 59%) as a yellow oil.

Step 4: Preparation of 6-(aminomethyl)isoquinolin-1-amine

To a solution of 1-aminoisoquinoline-6-carbonitrile (4.5 g, 26.47 mmol,1 eq) in MeOH (200 mL), DMF (200 mL) and ammonium hydroxide (100 mL) wasadded Raney Ni (4.0 g). The mixture was stirred at 40° C. overnightunder hydrogen atmosphere. Raney Ni was filtered off and the filtratewas concentrated in vacuo to give 6-(aminomethyl)isoquinolin-1-amine (3g, crude) as a yellow solid.

Intermediate 17: Preparation of (6-fluoro-1H-indol-5-yl)methanamine

Step 1: Preparation of6-fluoro-1-(triisopropylsilyl)-1H-indole-5-carbaldehyde

To a solution of 6-fluoro-1-(triisopropylsilyl)-1H-indole (2 g, 6.9mmol, 1.0 eq) in THF (30 mL) was added s-BuLi (6.3 mL, 1.3M, 1.2 eq) at−78° C. slowly. Then the mixture was stirred at this temperature for 1h. DMF (1.5 g, 20.7 mmol, 3.0 eq) was added dropwise. The mixture wasstirred at −78° C. for 1 h. Then the reaction was quenched by saturatedaqueous NH₄Cl. The obtained mixture was extracted with EtOAc (50 mL×3).The organic layers were combined and washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified on silicagel column (PE/EtOAc=100/1) to give6-fluoro-1-(triisopropylsilyl)-1H-indole-5-carbaldehyde as a yellow oil(950 mg, 57%).

Step 2: Preparation of 6-fluoro-1H-indole-5-carbaldehyde oxime

A mixture of 6-fluoro-1-(triisopropylsilyl)-1H-indole-5-carbaldehyde(780 mg, 2.45 mmol, 1.0 eq) and NH₂OH.HCl (340 mg, 4.89 mmol, 2.0 eq) inNH₃/MeOH (15% w/w, 10 mL) was stirred at rt overnight. The mixture wasconcentrated. The residue was purified directly on silica gel column(PE/EtOAc=50/1) to afford 6-fluoro-1H-indole-5-carbaldehyde oxime as ayellow solid (460 mg, crude).

Step 3: Preparation of (6-fluoro-1H-indol-5-yl)methanamine

A mixture of 6-fluoro-1H-indole-5-carbaldehyde oxime (460 mg, 1.38 mmol,1.0 eq) and Raney Ni (100 mg) in NH₃/MeOH (15% w/w, 10 mL) was stirredat rt under H₂ atmosphere (1 atm) overnight. Then the mixture wasfiltered and concentrated to afford (6-fluoro-1H-indol-5-yl)methanamineas a gray solid (420 mg, 95%). The solid was used for the next stepwithout further purification.

Intermediate 18: Preparation of(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methanamine

Step 1: Preparation of 5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

To a suspension of 5-chloro-1H-pyrrolo[2,3-b]pyridine (10.0 g, 65.5mmol, 1 eq) in AcOH (56.7 mL) and water (28.3 mL) was addedhexamethylenetetramine (11.9 g, 85.2 mmol, 1.3 eq). The mixture wasstirred under reflux overnight, followed by addition of 200 mL of water.After stirring for 30 min, the reaction mixture was filtered to recoverthe solid, then dried under air to give5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (6.2 g, 53%) as ayellow solid.

Step 2: Preparation of 5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehydeoxime

To a solution of 5-cloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1.0g, 5.55 mmol, 1 eq) in EtOH (40 mL) and water (10 mL) was addedhydroxylammonium chloride (575 mg, 8.33 mmol, 1.5 eq) and Na₂CO₃ (1.06g, 10.0 mmol, 1.8 eq). The mixture was stirred under reflux for 3 h andthen cooled to rt. The precipitate was collected by filtration to give5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde oxime (1.0 g, 92%) asan off white solid.

Step 3: Preparation of(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methanamine

To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde oxime(200 mg, 2 mmol, 1 eq) in MeOH (5 mL) was added NiCl₂ (128 mg, 1 mmol, 1eq) and NaBH₄ (228 mg, 6 mmol, 6 eq). The mixture was stirred at rt for5 h under hydrogen atmosphere. NiCl₂ was filtered off and the filtratewas concentrated in vacuo to give(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methanamine (65 mg, 30%) as ayellow solid.

Intermediate 19: Preparation of(5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methanamine

Step 1: Preparation of 1-(2-amino-5-chlorophenyl)-2-chloroethanone

To a stirred solution of boron trichloride in toluene (200 mL, 1M, 0.2mol, 1.16 eq), a solution of 4-chloroaniline (22.0 g, 0.172 mol, 1.0 eq)in dry toluene (200 mL) was added dropwise under nitrogen at atemperature ranging from 5° C. to 10° C. To the resulting mixture,chloroacetonitrile (15 mL, 0.237 mol, 1.38 eq) and aluminum trichloride(29.0 g, 0.217 mol, 1.26 eq) were added successively. The mixture wasrefluxed for 18 h. After cooling, ice-cold hydrochloric acid (2N, 500mL) was added and a yellow precipitate was formed. The mixture waswarmed at 80° C. with stirring, until the precipitate was dissolved. Thecooled solution was extracted with dichloromethane (250 mL×3). Theorganic layer was washed with water, dried (Na₂SO₄), and concentrated.The resulting residue was purified on silica gel column (PE/EtOAc=50/1PE/EtOAc/DCM=1/8/1, v/v/v) to afford1-(2-amino-5-chlorophenyl)-2-chloroethanone as a yellow brown solid(18.3 g, 52%).

Step 2: Preparation of 5-chloro-3-(chloromethyl)-1H-indazole

To a stirred suspension of 1-(2-amino-5-chlorophenyl)-2-chloroethanone(16 g, 78 mmol, 1.0 eq) in conc. hydrochloric acid (120 mL) was added asolution of sodium nitrite (5.9 g, 86 mmol, 1.1 eq) in water (30 mL) at0° C. After 1 h, a solution of SnCl₂.2H₂O (42.3 g, 187 mmol, 2.4 eq) inconc. hydrochloric acid (60 mL) was added to the reaction mixture andstirred for 1 h. Ice-water was added to the reaction mixture. Theprecipitate was collected by filtration, washed with water and dried toafford crude 5-chloro-3-(chloromethyl)-1H-indazole, which was used inthe next step without further purification (13.5 g, 86%).

Step 3: Preparation of5-chloro-3-(chloromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

A solution of 5-chloro-3-(chloromethyl)-1H-indazole (13.5 g, 67 mmol,1.0 eq), 3,4-dihydro-2H-pyran (11.3 g, 134 mmol, 2.0 eq) andp-toluenesulfonic acid monohydrate (1.27 g, 6.7 mmol, 0.1 eq) in THF(300 mL) was stirred at 70° C. for 12 h. After cooling to rt (−22° C.),the reaction mixture was mixed with water (300 mL) and extracted withethyl acetate (200 mL×2). The organic layer was washed with brine, driedover anhydrous Na₂SO₄, and concentrated to afford5-chloro-3-(chloromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as ayellow solid (16 g, 84%).

Step 4: Preparation of2-((5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methyl)isoindoline-1,3-dione

To a solution of5-chloro-3-(chloromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (18g, 63 mmol, 1 eq) in anhydrous DMF (200 mL) under N₂, potassiumphthalimide (17.5 g, 94 mmol, 1.5 eq) was added and the resultingmixture was heated at 90° C. for 2 h. The mixture was poured into waterand extracted with DCM (200 mL×2). The combined organic layers werewashed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated. The crude product was washed with EtOH to afford2-((5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methyl)isoindoline-1,3-dioneas a white solid (15 g, 60%).

Step 5: Preparation of(5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methanamine

To a solution of2-((5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methyl)isoindoline-1,3-dione(15 g, 37.9 mmol, 1.0 eq) in THF (300 mL) and DCM (60 mL) was addedhydrazine hydrate (9.5 g, 189 mmol, 5 eq). The white suspension wasstirred at 48° C. for 12 h and phthalyl hydrazide was removed byfiltration. The filtrate was concentrated in vacuo and the crudematerial was dissolved in DCM and washed with 1N NaOH solution. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated to afford(5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methanamine as ayellow solid (9.9 g, 99%).

Intermediate 20: Preparation of 5-(aminomethyl)-6-methylpyridin-2-amine

The solution of 6-amino-2-methylnicotinonitrile (200 mg, 1.5 mmol, 1.0eq) and Raney Ni (50 mg) in MeOH (10 mL) was stirred at rt under H₂ (1atm) overnight. Then the mixture was filtered and the filtrate wasconcentrated to give 5-(aminomethyl)-6-methylpyridin-2-amine as a yellowsolid (210 mg, quant). The solid was used without further purification.

Intermediate 21: Preparation of 5-(aminomethyl)-4-methylpyridin-2-amine

The solution of 6-amino-4-methylnicotinonitrile (200 mg, 1.5 mmol, 1.0eq) and Raney Ni (50 mg) in MeOH (10 mL) was stirred at rt under H₂ (1atm) overnight. Then the mixture was filtered and the filtrate wasconcentrated to give 5-(aminomethyl)-4-methylpyridin-2-amine as a yellowsolid (210 mg, quant). The solid was used without further purification.

Intermediate 22: Preparation of5-(aminomethyl)-6-(trifluoromethyl)pyridin-2-amine

The solution of 6-amino-2-(trifluoromethyl)nicotinonitrile (200 mg, 1.06mmol, 1.0 eq) and Raney Ni (50 mg) in MeOH (10 mL) was stirred at rtunder H₂ (1 atm) overnight. Then the mixture was filtered and thefiltrate was concentrated to give5-(aminomethyl)-6-(trifluoromethyl)pyridin-2-amine as a yellow solid(204 mg, quant). The solid was used without further purification.

Intermediate 23: Preparation of tert-butyl5-(aminomethyl)benzo[d]isoxazol-3-ylcarbamate

Step 1: Preparation of 5-methylbenzo[d]isoxazol-3-amine

Potassium tert-butylate (4.57 g, 40.8 mmol, 1.1 eq.) was suspended inTHF (40 mL). Acetone oxime (2.97 g, 40.7 mmol, 1.1 eq.) was added andthe mixture was stirred at rt for 20 min., followed by the addition of asolution of 2-fluoro-5-methylbenzonitrile (5.00 g, 37 mmol, 1.0 eq.) inTHF (30 mL) dropwise. The mixture was stirred at rt for 3 h and thenrefluxed overnight. The dark brown solution was quenched with water (10mL). The mixture was partitioned between saturated NaHCO₃ aqueoussolution (50 mL) and ethyl acetate (150 mL). The aqueous layer wasextracted with ethyl acetate (50 mL). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated to afford brown oil. Thecrude oil was dissolved in EtOH (80 mL). H₂O (53 mL) and conc. HCl (27mL) was added and the mixture was stirred at 90° C. for 2 h. Cooled tort and the mixture was basified with NaOH aqueous solution to pH 10. Theaqueous layer was extracted with ethyl acetate (100 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified via flash chromatography (PE/EtOAc=5/1, v/v) toafford 5-methylbenzo[d]isoxazol-3-amine as a white solid (2.5 g, 45.6%).

Step 2: Preparation of 5-methylbenzo[d]isoxazol-3-amine di(tert-butylcarbamate)

A mixture of 5-methylbenzo[d]isoxazol-3-amine (1.48 g, 10 mmol, 1.0eq.), Boc₂O (6.54 g, 30 mmol, 3.0 eq.), DMAP (122 mg, 1.0 mmol, 0.1eq.), TEA (4.2 mL, 30 mmol, 3.0 eq.) in DCM (30 mL) was refluxed for 18h. The mixture was washed with water (30 mL×2), dried over anhydrousNa₂SO₄ and concentrated. The residue was purified via flashchromatography (PE/EtOAc/DCM=1/20/1-1/7/1, v/v/v) to5-methylbenzo[d]isoxazol-3-amine di(tert-butyl carbamate) as a whitesolid (3.2 g, 92%).

Step 3: Preparation of 5-(bromomethyl)benzo[d]isoxazol-3-aminedi(tert-butyl carbamate)

A mixture of 5-methylbenzo[d]isoxazol-3-amine di(tert-buytl carbamate)(1.04 g, 3 mmol, 1.0 eq.), NBS (536 mg, 3 mmol, 1.0 eq.), AIBN (53 mg,0.32 mmol, 0.1 eq.) in CCl₄ (30 mL) was stirred at 85° C. for 5 h.Cooled to rt and the mixture was filtered. The filtrate was concentratedand the residue was purified via flash chromatography (PE/EtOAc=10/1,v/v) to afford 5-(bromomethyl)benzo[d]isoxazol-3-amine di(tert-butylcarbamate) as a white solid (970 mg, 75.8%).

Step 4: Preparation of2-((3-aminobenzo[d]isoxazol-5-yl)methyl)isoindoline-1,3-dionedi(tert-butyl carbamate)

A mixture of 5-(bromomethyl)benzo[d]isoxazol-3-amine di(tert-butylcarbamate) (602 mg, 1.4 mmol, 1.0 eq.), isoindoline-1,3-dione (310 mg,2.1 mmol, 1.5 eq.), Cs₂CO₃ (1.1 g, 3.4 mmol, 2.4 eq.) in DMF (10 mL) wasstirred at 20° C. overnight. The mixture was partitioned between ethylacetate (20 mL) and water (20 mL). The aqueous layer was extracted withethyl acetate (20 mL×2). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated. The residue was purified via flashchromatography (PE/EtOAc=5/1, v/v) to afford2-((3-aminobenzo[d]isoxazol-5-yl)methyl)isoindoline-1,3-dionedi(tert-butyl carbamate) as a white solid (616 mg, 88.8%).

Step 5: Preparation of tert-butyl5-(aminomethyl)benzo[d]isoxazol-3-ylcarbamate

To a solution of2-((3-aminobenzo[d]isoxazol-5-yl)methyl)isoindoline-1,3-dionedi(tert-butyl carbamate) (320 mg, 0.65 mmol, 1.0 eq.) in n-BuOH (10 mL)was added NH₂NH₂.H₂O (0.20 mL). The mixture was stirred at rt overnight.The white slurry was diluted with DCM (10 mL) and filtered. The filtratewas evaporated and to the residue was triturated with Et₂O and dried toafford tert-butyl 5-(aminomethyl)benzo[d]isoxazol-3-ylcarbamate as awhite solid (120 mg, 70.6%).

Intermediate 24: Preparation of2-((6-methyl-2-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinic acid

Step 1: Preparation of2-methanesulfonyl-6-methyl-quinoline-3-carbaldehyde

To a suspension of 2-chloro-6-methyl-quinoline-3-carbaldehyde (1.0 g,4.88 mmol, 1 eq) in DMF (30 mL) was added sodium methanesulfinate (1.49g, 14.6 mmol, 3 eq). The reaction mixture was stirred at 100° C. for 1 hunder nitrogen. The cooled mixture was partitioned between EtOAc andwater. The organic layer was separated and concentrated, and theresulting residue was purified by chromatography on silica gel column(EtOAc/PE=1/2, v/v) to give2-methanesulfonyl-6-methyl-quinoline-3-carbaldehyde (1.1 g, 90%) as ayellow solid.

Step 2: Preparation of(2-methanesulfonyl-6-methyl-quinolin-3-yl)-methanol

To a solution of 2-methanesulfonyl-6-methyl-quinoline-3-carbaldehyde(400 mg, 1.61 mmol, 1 eq) in MeOH (20 mL) was added NaBH₄ (67 mg, 1.77mmol, 1.1 eq). The reaction mixture was stirred at 0° C. for 1 h. Themixture was partitioned between DCM and water. The organic layer wasseparated and concentrated. The resulting residue was purified bychromatography on silica gel column (EtOAc/PE=1/2, v/v) to give(2-methanesulfonyl-6-methyl-quinolin-3-yl)-methanol (395 mg, 97%) as ayellow solid.

Step 3: Preparation of3-chloromethyl-2-methanesulfonyl-6-methyl-quinoline

A mixture of (2-methanesulfonyl-6-methyl-quinolin-3-yl)-methanol (395mg, 1.57 mmol, 1.0 eq) in SOCl₂ (10 mL) was stirred at rt for 1 h andconcentrated. The resulting residue was dissolved in DCM and treatedwith saturated NaHCO₃ solution. The organic layer was concentrated togive 3-chloromethyl-2-methanesulfonyl-6-methyl-quinoline (400 mg, 95%)as a yellow solid.

Step 4: Preparation of methyl2-((6-methyl-2-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinate

To a solution of 3-chloromethyl-2-methanesulfonyl-6-methyl-quinoline(400 mg, 1.49 mmol, 1.0 eq) in dioxane (15 mL) was added methyl2-(trimethylstannyl)isonicotinate (492 mg, 1.64 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (105 mg, 0.15 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, stripped of solvent and finallypurified by chromatography on silica gel column (DCM/MeOH=100/1, v/v) toafford methyl2-((6-methyl-2-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinate (100mg, 18%) as a yellow solid.

Step 5: Preparation of2-((6-methyl-2-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinic acid

To a solution of2-((6-methyl-2-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinate (100mg, 0.27 mmol, 1 eq) in THF/H₂O (5 mL, 1:1) was added LiOH.H₂O (17 mg,0.41 mmol, 1.5 eq). The mixture was stirred at rt for 1 h and themixture was acidified to pH 3 with 1N HCl solution. The solvent wasremoved to give2-((6-methyl-2-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinic acid asa yellow solid which was used in the next step without furtherpurification.

Intermediate 25: Preparation of2-((3-cyanoquinolin-6-yl)methyl)isonicotinic acid

Step 1: Preparation of (3-bromo-quinolin-6-yl)-methanol

To a solution of methyl 3-bromoquinoline-6-carboxylate (4.5 g, 17.0mmol, 1 eq) in THF (200 mL) was added LiAlH(t-BuO)₃ (10.78 g, 42.5 mmol,2.5 eq). The resulting mixture was stirred at 40° C. for 12 h and thenquenched by the addition of water. The mixture was extracted with EtOAc.The combined extracts were dried and concentrated. The resulting residuewas purified by chromatography on silica gel column (PE/EtOAc=2/1, v/v)to afford (3-bromo-quinolin-6-yl)-methanol (3.1 g, 78%) as a yellowsolid.

Step 2: Preparation of 6-hydroxymethyl-quinoline-3-carbonitrile

To a solution of (3-bromo-quinolin-6-yl)-methanol (3.1 g, 13.1 mmol, 1eq) in DMF (60 mL) was added Zn(CN)₂ (1.52 g, 13.1 mmol, 1 eq) andPd(PPh₃)₄ (757 mg, 0.66 mmol, 0.05 eq). The mixture was stirred at 90°C. overnight and then cooled to rt. The precipitate was filtered off andthe filtrate was concentrated. The residue was purified by flashchromatography on silica gel column (PE/EtOAc=2/1, v/v) to give6-hydroxymethyl-quinoline-3-carbonitrile (1.95 g, 81%) as a yellowsolid.

Step 3: Preparation of 6-chloromethyl-quinoline-3-carbonitrile

A mixture of 6-hydroxymethyl-quinoline-3-carbonitrile (1.95 g, 10.6mmol, 1.0 eq) in SOCl₂ (50 mL) was stirred at rt for 1 h andconcentrated. The residue was dissolved in DCM and treated withsaturated NaHCO₃ solution. The organic layer was concentrated to give6-chloromethyl-quinoline-3-carbonitrile (2.0 g, 93%) as a yellow solid.

Step 4: Preparation of methyl2-((3-cyanoquinolin-6-yl)methyl)isonicotinate

To a solution of 6-chloromethyl-quinoline-3-carbonitrile (2.0 g, 10.9mmol, 1 eq) in dioxane (60 mL) was added methyl2-(trimethylstannyl)isonicotinate (3.60 g, 12.0 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (770 mg, 0.11 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, stripped of solvent and finallypurified by chromatography on silica gel column (DCM/MeOH=100/1, v/v) toafford methyl 2-((3-cyanoquinolin-6-yl)methyl)isonicotinate (750 mg,23%) as a yellow solid.

Step 5: Preparation of 2-((3-cyanoquinolin-6-yl)methyl)isonicotinic

To a solution of methyl 2-((3-cyanoquinolin-6-yl)methyl)isonicotinate(750 mg, 2.47 mmol, 1 eq) in THF/H₂O (20 mL, 1:1) was added LiOH.H₂O(156 mg, 3.71 mmol, 1.5 eq). The mixture was stirred at rt for 1 h, andthen it was acidified to pH 3 with 1N HCl solution. The solvent wasconcentrated to give 2-((3-cyanoquinolin-6-yl)methyl)isonicotinic acidas a yellow solid which was used in the next step without furtherpurification.

Intermediate 26: Preparation of2-((3-chloro-8-(methoxycarbonyl)quinolin-6-yl)methyl)isonicotinic acid

Step 1: Preparation of methyl 3-chloro-8-iodoquinoline-6-carboxylate

To a solution of methyl 8-iodoquinoline-6-carboxylate (30 g, 96 mmol,1.0 eq) in AcOH (1.0 L) was added NCS (38 g, 293 mmol, 3 eq). Themixture was stirred at 100° C. overnight, The mixture was concentratedin vacuo and the residue was purified by chromatography on silica gelcolumn (PE/DCM=1/1, v/v) to afford methyl3-chloro-8-iodoquinoline-6-carboxylate (15 g, 49%) as yellow solid.

Step 2: Preparation of (3-chloro-8-iodo-quinolin-6-yl)-methanol

To a solution of methyl 3-chloro-8-iodoquinoline-6-carboxylate (12 g,34.5 mmol, 1.0 eq) in dry THF (200 mL) was added lithiumtri-tert-butoxyaluminum hydride (22 g, 70 mmol, 3.4 eq) carefully. Themixture was stirred at 50° C. for 5 h under N₂ protected. Then EtOAc andwater was added. The organic layer was concentrated, and purified bychromatography on silica gel column (PE/DCM=1/1, v/v) to afford(3-chloro-8-iodo-quinolin-6-yl)-methanol (7.6 g, 69%) as white solid.

Step 3: Preparation of 3-chloro-6-hydroxymethyl-quinoline-8-carbonitrile

To a solution of (3-chloro-8-iodo-quinolin-6-yl)-methanol (7.6 g, 23.8mmol, 1.0 eq) in DMF (100 mL) was added Zn(CN)₂ (2.79 g, 23.8 mmol, 1.0eq) and Pd(PPh₃)₄ (2.75 g, 2.38 mmol, 0.1 eq) carefully. The mixture wasstirred at 50° C. overnight under N₂ protected. Then EtOAc and water wasadded. The organic layer was concentrated, and purified bychromatography on silica gel column (PE/DCM=1/2, v/v) to afford3-chloro-6-hydroxymethyl-quinoline-8-carbonitrile (5.0 g, 96%) as yellowsolid.

Step 4: Preparation of 3-chloro-6-chloromethyl-quinoline-8-carbonitrile

A mixture of 3-chloro-6-hydroxymethyl-quinoline-8-carbonitrile (2.9 g,13.3 mmol, 1.0 eq) in SOCl₂ (50 mL) was stirred at rt for 1 h andconcentrated. The residue was dissolved in DCM and treated withsaturated NaHCO₃ solution to give3-chloro-6-chloromethyl-quinoline-8-carbonitrile (2.2 g, 70%) as ayellow solid.

Step 5: Preparation of methyl2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinate

To a solution of 3-chloro-6-chloromethyl-quinoline-8-carbonitrile (2.0g, 8.47 mmol, 1.0 eq) in dioxane (40 mL) was added methyl2-(trimethylstannyl)isonicotinate (2.8 g, 9.32 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (597 mg, 0.85 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, concentrated and purified bychromatography on silica gel column (DCM/MeOH=100/1, v/v) to affordmethyl 2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinate (1.4 g,49%) as a yellow solid.

Step 6: Preparation of methyl3-chloro-6-((4-(methoxycarbonyl)pyridin-2-yl)methyl)quinoline-8-carboxylate

A mixture of methyl2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinate (1.20 g, 3.56mmol, 1 eq) in HCl/MeOH (10N, 100 mL) was heated under 80° C. for 7 daysand then concentrated. The residue was dissolved in DCM and treated withsaturated NaHCO₃ solution. The organic layer was concentrated and theresidue was purified by flash chromatography on silica gel column(PE/EtOAc=1/1, v/v) to give methyl3-chloro-6-((4-(methoxycarbonyl)pyridin-2-yl)methyl)quinoline-8-carboxylate(900 mg, 68%) as a yellow solid.

Step 7: Preparation of2-((3-chloro-8-(methoxycarbonyl)quinolin-6-yl)methyl)isonicotinic acid

To a solution of methyl3-chloro-6-((4-(methoxycarbonyl)pyridin-2-yl)methyl)quinoline-8-carboxylate(900 mg, 2.43 mmol, 1 eq) in THF/H₂O (20 mL, 1:1) was added LiOH.H₂O(102 mg, 2.43 mmol, 1.0 eq). The mixture was stirred at rt for 1 h andthe mixture was acidified to pH 3 with 1N HCl solution. The mixture wasextracted with DCM and the combined organic layers were dried andconcentrated. The residue was purified by flash chromatography on silicagel column (DCM/MeOH=10/1, v/v) to give2-((3-chloro-8-(methoxycarbonyl)quinolin-6-yl)methyl)isonicotinic acid(400 mg, 46%) as a yellow solid.

Intermediate 27: Preparation of2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinic acid

Step 1: Preparation of methyl 4-amino-3-iodobenzoate

To a solution of methyl 4-aminobenzoate (20 g, 0.132 mol, 1 eq) in AcOH(500 mL) was added a solution of ICl (23.6 g, 0.146 mol, 1.1 eq) in AcOH(500 mL) at 0° C. The mixture was stirred at rt for 2 h. AcOH wasconcentrated under reduced pressure. The residue was diluted with DCMand washed with saturated NaHCO₃. The aqueous layer was extracted withDCM and the combined extracts were dried and concentrated. The resultingresidue was purified by chromatography on silica gel column(EtOAc/PE=1/15, v/v) to give methyl 4-amino-3-iodobenzoate (27.4 g, 75%)as an off-white solid.

Step 2: Preparation of methyl 8-iodo-3-methylquinoline-6-carboxylate

A mixture of methyl 4-amino-3-iodobenzoate (26 g, 93.5 mmol),2-methyl-propenal (24.5 g, 0.28 mol, 3 eq) and 6N HCl (95 mL) was heatedto reflux for 24 h. Then the mixture was cooled and adjusted to pH˜5-6using saturated NaHCO₃. The mixture was extracted with DCM. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered thenconcentrated and purified by chromatography on silica gel column(EtOAc/PE=1/20, v/v) to give methyl8-iodo-3-methylquinoline-6-carboxylate (10.2 g, 33%) as a yellow solid.

Step 3: Preparation of (8-iodo-3-methyl-quinolin-6-yl)-methanol

To a solution of methyl 8-iodo-3-methylquinoline-6-carboxylate (7.5 g,22.9 mmol, 1 eq) in THF (200 mL) was added LiAlH(t-BuO)₃ (14.6 g, 57.3mmol, 2.5 eq). The resulting mixture was stirred at 40° C. for 12 h andthen quenched by the addition of water. The mixture was extracted withEtOAc. The combined extracts were dried and concentrated. The resultingresidue was purified by chromatography on silica gel column(PE/EtOAc=2/1, v/v) to afford (8-iodo-3-methyl-quinolin-6-yl)-methanol(6.5 g, 95%) as a yellow solid.

Step 4: Preparation of 6-hydroxymethyl-3-methyl-quinoline-8-carbonitrile

To a solution of (8-iodo-3-methyl-quinolin-6-yl)-methanol (2.1 g, 7.0mmol, 1 eq) in DMF (50 mL) was added Zn(CN)₂ (815 mg, 7.0 mmol, 1 eq)and Pd(PPh₃)₄ (404 mg, 0.35 mmol, 0.05 eq). The mixture was stirred at90° C. overnight and then cooled to rt. The precipitate was filtered offand the filtrate was concentrated. The resulting residue was purified byflash chromatography on silica gel column (PE/EtOAc=2/1, v/v) to give6-hydroxymethyl-3-methyl-quinoline-8-carbonitrile (1.2 g, 86%) as ayellow solid.

Step 5: Preparation of 6-chloromethyl-quinoline-3-carbonitrile

A mixture of 6-hydroxymethyl-3-methyl-quinoline-8-carbonitrile (1.2 g,6.06 mmol, 1.0 eq) in SOCl₂ (30 mL) was stirred at rt for 1 h andconcentrated. The residue was dissolved in DCM and treated withsaturated NaHCO₃ solution. The organic layer was concentrated to give6-chloromethyl-quinoline-3-carbonitrile (1.2 g, 92%) as a yellow solid.

Step 6: Preparation of methyl2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinate

To a solution of 6-chloromethyl-quinoline-3-carbonitrile (1.2 g, 5.55mmol, 1 eq) in dioxane (60 mL) was added methyl2-(trimethylstannyl)isonicotinate (1.84 g, 6.11 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (428 mg, 0.61 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, stripped of solvent and finallypurified by chromatography on silica gel column (DCM/MeOH=100/1, v/v) toafford methyl 2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinate(1.1 g, 62%) as a yellow solid.

Step 7: Preparation of2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinic acid

To a solution of methyl2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinate (1.1 g, 3.47mmol, 1 eq) in THF/H₂O (30 mL, 1:1) was added LiOH.H₂O (219 mg, 5.21mmol, 1.5 eq). The mixture was stirred at rt for 1 h and the mixture wasacidified to pH 3 with 1N HCl solution. The mixture was extracted withDCM, and the combined organic layers were dried and concentrated give2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinic acid (950 mg, 91%)as a white solid which was used without further purification.

Intermediate 28: Preparation of2-((3-methyl-1H-indol-5-yl)methyl)isonicotinic acid

Step 1: Preparation of methyl 3-chloro-1H-indole-5-carboxylate

To a solution of methyl 1H-indole-5-carboxylate (10.0 g, 57.1 mmol, 1.0eq) in MeOH was added NCS (8.4 g, 62.8 mmol, 1.1 eq). The mixture wasstirred at rt for 3 h. MeOH was removed, and the resulting residue wasdissolved in EtOAc. The mixture was washed with brine twice. The organiclayer was dried and concentrated to give methyl3-chloro-1H-indole-5-carboxylate (quant.) as a yellow solid.

Step 2: Preparation of 1-tert-butyl 5-methyl3-chloro-1H-indole-1,5-dicarboxylate

To a solution of methyl 3-chloro-1H-indole-5-carboxylate (11.9 g, 57.1mmol, 1.0 eq) in MeOH was added Boc₂O (18.7 g, 86.7 mmol, 1.5 eq) andDMAP (348 mg, 2.86 mmol, 0.05 eq). The mixture was stirred at rt for 2h. The mixture was concentrated and purified by chromatography on silicagel column (EtOAc/PE=1/10, v/v) to give 1-tert-butyl 5-methyl3-chloro-1H-indole-1,5-dicarboxylate (13.4 g, 76%) as an off-whitesolid.

Step 3: Preparation of tert-butyl3-chloro-5-(hydroxymethyl)-1H-indole-1-carboxylate

To a solution of 1-tert-butyl 5-methyl3-chloro-1H-indole-1,5-dicarboxylate (7.0 g, 22.6 mmol, 1 eq) in THF(100 mL) was added LiAlH(t-BuO)₃ (14.4 g, 56.6 mmol, 2.5 eq). Theresulting mixture was stirred at 60° C. for 12 h and then quenched bythe addition of water. The mixture was extracted with EtOAc. Thecombined extracts were dried and concentrated. The resulting residue waspurified by chromatography on silica gel column (PE/EtOAc=2/1, v/v) toafford tert-butyl 3-chloro-5-(hydroxymethyl)-1H-indole-1-carboxylate(4.3 g, 68%) as a white solid.

Step 4: Preparation of tert-butyl3-chloro-5-(chloromethyl)-1H-indole-1-carboxylate

To a solution of tert-butyl3-chloro-5-(hydroxymethyl)-1H-indole-1-carboxylate (1.5 g, 5.34 mmol, 1eq) in dry DCM (30 mL) was added Et₃N (1.5 mL, 10.68 mmol, 2 eq) andMsCl (0.62 mL, 8.01 mmol, 1.5 eq). The resulting mixture was stirred atrt for 24 h and then quenched by the addition of water. The mixture wasextracted with DCM. The combined extracts were dried and concentrated.The resulting residue was purified by chromatography on silica gelcolumn (PE/EtOAc=20/1, v/v) to afford tert-butyl3-chloro-5-(chloromethyl)-1H-indole-1-carboxylate (1.17 g, 73%) as awhite solid.

Step 5: Preparation of tert-butyl3-chloro-5-((4-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-indole-1-carboxylate

To a solution of tert-butyl3-chloro-5-(chloromethyl)-1H-indole-1-carboxylate (1.1 g, 3.68 mmol, 1.0eq) in dioxane (20 mL) were added methyl2-(trimethylstannyl)isonicotinate (1.22 g, 4.05 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (260 mg, 0.37 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, concentrated and purified bychromatography on silica gel column (PE/EtOAc=20/1, v/v) to affordtert-butyl3-chloro-5-((4-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-indole-1-carboxylate(690 mg, 47%) as an off-white solid.

Step 6: Preparation of tert-butyl5-((4-(methoxycarbonyl)pyridin-2-yl)methyl)-3-methyl-1H-indole-1-carboxylate

To a solution of tert-butyl3-chloro-5-((4-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-indole-1-carboxylate(400 mg, 1.0 mmol, 1 eq) in 1,4-dioxane (10 mL) was added potassiumphosphate (424 mg, 2 mmol, 2 eq), trimethylboroxine (504 mg, 2 mmol, 2eq, 50% purity in THF), tris(dibenzylideneacetone)dipalladium (46 mg,0.05 mmol, 0.05 eq) and2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-Phos)(134 mg, 0.30 mmol, 0.30 eq) under argon, and the mixture was heated to110° C. and stirred for 4 h. Ice cooled water was then added, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried, and then concentrated under reduced pressure. Theresulting residue was purified by chromatography on silica gel column(EtOAc/PE=1/5, v/v) to give tert-butyl5-((4-(methoxycarbonyl)pyridin-2-yl)methyl)-3-methyl-1H-indole-1-carboxylate(280 mg, 74%) as a yellow solid.

Step 7: Preparation of 2-((3-methyl-1H-indol-5-yl)methyl)isonicotinicacid

To a solution of tert-butyl5-((4-(methoxycarbonyl)pyridin-2-yl)methyl)-3-methyl-1H-indole-1-carboxylate(280 mg, 0.74 mmol, 1 eq) in DCM (3 mL) was added TFA (3 mL). Themixture was stirred at rt for 2 h and then concentrated. The residue wasdiluted with DCM and washed with saturated NaHCO₃. The organic layer wasconcentrated and the residue was dissolved in THF/H₂O (10 mL, 1:1). Tothe mixture was added LiOH.H₂O (47 mg, 1.11 mmol, 1.5 eq). The mixturewas stirred at rt for 1 h and the mixture was acidified to pH 3 with 1NHCl solution. The mixture was extracted with DCM, and the combinedorganic layers were dried and concentrated give2-((3-methyl-1H-indol-5-yl)methyl)isonicotinic acid (99 mg, 50%) as ayellow solid.

Intermediate 29: Preparation of2-((2-(acetamidomethyl)quinolin-6-yl)methyl)isonicotinic acid

Step 1: Preparation of 6-(methoxycarbonyl)quinoline 1-oxide

A mixture of methyl quinoline-6-carboxylate (10 g, 53.5 mmol, 1 eq) andm-CPBA (18.4 g, 0.106 mol, 2 eq) in DCM (50 mL) was stirred at rtovernight. Saturated aq. NaHCO₃ (40 mL) was added to the reactionmixture, and the resulting mixture was stirred for 30 min. The organiclayer was separated, dried, filtered and concentrated. The resultingresidue was recrystallized in EtOAc (5 mL) to afford6-(methoxycarbonyl)quinoline 1-oxide (8.0 g, 74%) as a light yellowsolid.

Step 2: Preparation of methyl 2-chloroquinoline-6-carboxylate and methyl4-chloroquinoline-6-carboxylate

To 6-(methoxycarbonyl)quinoline 1-oxide (4.0 g, 19.7 mmol, 1 eq) wasadded phosphoryl trichloride (20 mL). The resulting mixture was thenstirred at rt under N₂ for 2 h. The volatiles were then removed undervacuum and the residue was dissolved in DCM. The mixture was washed withsaturated aq. NaHCO₃, dried and concentrated. The resulting residue waspurified by chromatography on silica gel column (PE/EtOAc=10/1, v/v) toafford methyl 2-chloroquinoline-6-carboxylate (1.2 g, 28%) and methyl4-chloroquinoline-6-carboxylate (2.5 g, 57%).

Step 3: Preparation of methyl 2-cyanoquinoline-6-carboxylate

To a suspension of methyl 2-chloroquinoline-6-carboxylate (1.2 g, 5.43mmol, 1 eq) in DMF (15 mL) was added Zn(CN)₂ (1.11 g, 10.86 mmol, 2 eq)and Pd(PPh₃)₄ (628 mg, 0.54 mmol, 0.1 eq). The reaction mixture wasstirred at 100° C. for 3 h under nitrogen. The cooled mixture waspartitioned between EtOAc and water. The organic layer was separated andconcentrated. The resulting residue was purified by chromatography onsilica gel column to give methyl 2-cyanoquinoline-6-carboxylate (980 mg,85%) as a yellow solid.

Step 4: Preparation of 6-hydroxymethyl-quinoline-2-carbonitrile

To a suspension of methyl 2-cyanoquinoline-6-carboxylate (980 mg, 462mmol. 1 eq) in dry THF (30 mL) was added LiAlH(t-BuO)₃ (2.94 g, 11.56mmol, 2.5 eq). The resulting mixture was stirred at 60° C. for 12 h andthen quenched by the addition of water. The mixture was extracted withEtOAc. The combined extracts were dried and concentrated. The resultingresidue was purified by chromatography on silica gel column(PE/EtOAc=1/2, v/v) to afford 6-hydroxymethyl-quinoline-2-carbonitrile(722 mg, 83%) as a yellow solid.

Step 5: Preparation of 6-chloromethyl-quinoline-2-carbonitrile

To 6-hydroxymethyl-quinoline-2-carbonitrile (2.1 g, 11.41 mmol, 1 eq)was added SOCl₂ (50 mL) and the mixture was stirred at rt for 3 h. Thevolatiles were then removed at 40° C. under vacuum and the residue wasdissolved in DCM. The mixture was washed with saturated NaHCO₃ solution,dried and concentrated to give 6-chloromethyl-quinoline-2-carbonitrile(2.10 g, 91%) as a yellow solid.

Step 6: Preparation of methyl2-((2-cyanoquinolin-6-yl)methyl)isonicotinate

To a solution of 6-chloromethyl-quinoline-2-carbonitrile (2.10 g, 10.40mmol, 1.0 eq) in dioxane (50 mL) was added methyl2-(trimethylstannyl)isonicotinate (3.44 g, 11.44 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (730 mg, 1.04 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen, concentrated and purified by chromatographyon silica gel column (DCM/MeOH=100/1, v/v) to afford methyl2-((2-cyanoquinolin-6-yl)methyl)isonicotinate (1.42 g, 45%) as a yellowsolid.

Step 7: Preparation of methyl2-((2-((tert-butoxycarbonylamino)methyl)quinolin-6-yl)methyl)isonicotinate

To a solution of methyl 2-((2-cyanoquinolin-6-yl)methyl)isonicotinate(1.0 g, 3.30 mmol, 1 eq) in MeOH (30 mL) were added Boc₂O (1.08 g, 5.00mmol, 1.5 eq) and Raney Ni (200 mg). The mixture was stirred at rt for 5h under hydrogen. Raney Ni was removed by filtration and the filtratewas concentrated. The resulting residue was purified by chromatographyon silica gel column (EtOAc/PE=1/2, v/v) to afford methyl2-((2-((tert-butoxycarbonylamino)methyl)quinolin-6-yl)methyl)isonicotinate(1.1 g, 82%) as a yellow solid.

Step 8: Preparation of methyl2-((2-(acetamidomethyl)quinolin-6-yl)methyl)isonicotinate

To a solution of methyl2-((2-((tert-butoxycarbonylamino)methyl)quinolin-6-yl)methyl)isonicotinate(1.1 g, 2.70 mmol, 1 eq) in EtOAc (5 mL) was added a solution ofHCl/EtOAc (30 mL, 10N). The mixture was stirred at rt for 2 h, and theprecipitate was collected by filtration. To a suspension of the aboveobtained crude product in DCM (30 mL) were added TEA (818 mg, 8.10 mmol,3 eq) and AcCl (316 mg, 4.05 mmol, 1.5 eq). The mixture was stirred atrt for 1 h and the mixture was concentrated. The resulting residue waspurified by chromatography on silica gel column (EtOAc/PE=1/2, v/v) toafford methyl 2-((2-(acetamidomethyl)quinolin-6-yl)methyl)isonicotinate(744 mg, 79% for 2 steps) as a yellow solid.

Step 9: Preparation of2-[2-(acetylamino-methyl)-quinolin-6-ylmethyl]-isonicotinic acid

To a solution of methyl2-((2-(acetamidomethyl)quinolin-6-yl)methyl)isonicotinate (744 mg, 2.13mmol, 1 eq) in THF/H₂O (30 mL, 1:1) was added LiOH.H₂O (134 mg, 3.20mmol, 1.5 eq). The mixture was stirred at rt for 1 h, and acidified topH 3 with 1N HCl solution. The mixture was extracted with DCM. Theorganic layer was washed with brine and then dried and concentrated togive 2-[2-(acetylamino-methyl)-quinolin-6-ylmethyl]-isonicotinic acid(649 mg, 91%) as a yellow solid which was used without furtherpurification.

Intermediate 30: Preparation of2-((2-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinic acid

Step 1: Preparation of methyl 2-(methylsulfonyl)quinoline-6-carboxylate

A mixture of methyl 2-chloroquinoline-6-carboxylate (1.2 g, 5.43 mmol, 1eq), sodium methanesulphinate (665 mg, 6.51 mmol, 1.2 eq), copper iodide(103 mg, 0.54 mol, 0.1 eq), L-proline sodium salt (148 mg, 1.08 mol, 0.2eq) in 110 mL of DMSO was heated to 110° C. under nitrogen and stirredfor 15 h. The cooled mixture was partitioned between ethyl acetate andwater. The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate twice. The combined organic layers werewashed with brine, dried over MgSO₄, and concentrated in vacuo. Theresulting residue was purified by chromatography on silica gel column(EtOAc/PE=1/2, v/v) to give methyl2-(methylsulfonyl)quinoline-6-carboxylate (830 mg, 58%) as a yellowsolid.

Step 2: Preparation of (2-methanesulfonyl-quinolin-6-yl)-methanol

To a solution of methyl 2-(methylsulfonyl)quinoline-6-carboxylate (830mg, 3.13 mmol, 1 eq) in THF (40 mL) was added LiAlH(t-BuO)₃ (2.0 g, 7.83mmol, 2.5 eq). The resulting mixture was stirred at 40° C. for 12 h andthen quenched by the addition of water. The mixture was extracted withEtOAc. The combined extracts were dried and concentrated. The resultingresidue was purified by chromatography on silica gel column(PE/EtOAc=1/1, v/v) to afford (2-methanesulfonyl-quinolin-6-yl)-methanol(600 mg, 81%) as a yellow solid.

Step 3: Preparation of 6-chloromethyl-2-methanesulfonyl-quinoline

A mixture of (2-methanesulfonyl-quinolin-6-yl)-methanol (580 mg, 2.48mmol, 1.0 eq) in SOCl₂ (10 mL) was stirred at rt for 1 h andconcentrated. The residue was dissolved in DCM and treated withsaturated NaHCO₃ solution. The organic layer was concentrated to give6-chloromethyl-2-methanesulfonyl-quinoline (570 mg, 90%) as a yellowsolid.

Step 4: Preparation of methyl2-((2-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinate

To a solution of 6-chloromethyl-2-methanesulfonyl-quinoline (560 mg,2.20 mmol, 1.0 eq) in dioxane (15 mL) was added methyl2-(trimethylstannyl)isonicotinate (727 mg, 2.42 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (154 mg, 0.22 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen, concentrated and purified by chromatographyon silica gel column (DCM/MeOH=100/1, v/v) to afford methyl2-((2-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinate (140 mg, 18%)as a yellow solid.

Step 5: Preparation of2-((2-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinic acid

To a solution of methyl2-((2-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinate (140 mg, 0.39mmol, 1 eq) in THF/H₂O (5 mL, 1:1) was added LiOH.H₂O (25 mg, 0.59 mmol,1.5 eq). The mixture was stirred at rt for 1 h, and acidified to pH 3with 1N HCl solution. The solvent was removed to give2-((2-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinic acid as a yellowsolid which was used in the next step without further purification.

Intermediate 31: Preparation of(3-chloro-4-fluoro-1H-indol-5-yl)methanamine hydrochloride

Step 1: Preparation of 4-fluoro-1-triisopropylsilanyl-1H-indole

To a solution of 4-fluoro-1H-indole (5.0 g, 37.04 mmol, 1.0 eq) in dryTHF (200 mL) was added a solution of NaH (1.63 g, 40.74 mmol, 1.1 eq,60% purity) at 0° C. After stirring for 0.5 h, TIPSCl (7.8 g, 40.74mmol, 1.1 eq) was added. Then the mixture was stirred at rt for 1 h andquenched by the addition of water. The mixture was extracted with EtOAc.The combined organic layers were dried and concentrated. The resultingresidue was purified by chromatography on silica gel column(PE/EtOAc=10/1, v/v) to afford 4-fluoro-1-triisopropylsilanyl-1H-indole(10.0 g, 84%) as a yellow oil.

Step 2: Preparation of4-fluoro-1-(triisopropylsilyl)-1H-indole-5-carbaldehyde

To a solution of 4-fluoro-1-triisopropylsilanyl-1H-indole (10 g, 34.36mmol, 1.0 eq) in THF (30 mL) was added s-BuLi (27.5 mL, 41.24 mmol,1.5M, 1.2 eq) at −78° C. slowly. The mixture was stirred for 1 h. DMF(7.52 g, 103 mmol, 3.0 eq) was added dropwise. The mixture was stirredat −78° C. for 1 h. The reaction was quenched by saturated aq. NH₄Cl.The mixture was extracted with EtOAc (50 mL×3). The organic layers werecombined and washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography on silica gelcolumn (PE/EtOAc=100/1) to give4-fluoro-1-(triisopropylsilyl)-1H-indole-5-carbaldehyde (6.6 g, 60%) asa yellow oil.

Step 3: Preparation of 4-fluoro-1H-indole-5-carbaldehyde oxime

A mixture of 4-fluoro-1-(triisopropylsilyl)-1H-indole-5-carbaldehyde(6.5 g, 20.4 mmol, 1.0 eq) and NH₂OH.HCl (2.82 g, 40.8 mmol, 2.0 eq) inNH₃/MeOH (15% w/w, 200 mL) was stirred at rt overnight. The mixture wasconcentrated. The residue was purified by chromatography on silica gelcolumn (PE/EtOAc=50/1) to afford 4-fluoro-1H-indole-5-carbaldehyde oxime(3.6 g, crude) as a yellow solid.

Step 4: Preparation of (4-fluoro-1H-indol-5-yl)methanamine

A mixture of 4-fluoro-1H-indole-5-carbaldehyde oxime (3.6 g, 20.2 mmol,1.0 eq) and Raney Ni (600 mg) in NH₃/MeOH (15% w/w, 200 mL) was stirredat rt under H₂ atmosphere (1 atm) overnight. The mixture was filteredand concentrated to afford (4-fluoro-1H-indol-5-yl)methanamine (3.0 g,92%) as a gray solid, which was used in the next step without furtherpurification.

Step 5: Preparation of tert-butyl(4-fluoro-1H-indol-5-yl)methylcarbamate

To a solution of (4-fluoro-1H-indol-5-yl)methanamine (3.0 g, 18.3 mmol,1.0 eq) in DCM (150 mL) was added TEA (2.22 g, 22.0 mmol, 1.2 eq) andBoc₂O (4.80 g, 22.0 mmol, 1.2 eq). The mixture was stirred at rt for 2 hand concentrated. The residue was purified by chromatography on silicagel column (PE/EtOAc=10/1, v/v) to afford tert-butyl(4-fluoro-1H-indol-5-yl)methylcarbamate (4.2 g, 87%) as a yellow solid.

Step 6: Preparation of tert-butyl(3-chloro-4-fluoro-1H-indol-5-yl)methylcarbamate

To a solution of tert-butyl (4-fluoro-1H-indol-5-yl)methylcarbamate (4.2g, 15.9 mmol, 1.0 eq) in DCM (150 mL) was added NCS (2.22 g, 16.7 mmol,1.05 eq). The mixture was stirred at rt for 1 h and concentrated. Theresidue was purified by chromatography on silica gel column(PE/EtOAc=10/1, v/v) to afford tert-butyl(3-chloro-4-fluoro-1H-indol-5-yl)methylcarbamate (4.0 g, 85%) as ayellow solid.

Step 7: Preparation of (3-chloro-4-fluoro-1H-indol-5-yl)methanaminehydrochloride

To a solution of tert-butyl(3-chloro-4-fluoro-1H-indol-5-yl)methylcarbamate (4.0 g, 13.4 mmol, 1.0eq) in EtOAc (20 mL) was added a solution of HCl in EtOAc (10N, 80 mL).The mixture was stirred at rt for 1 h, and the precipitate was collectedby filtration to afford (3-chloro-4-fluoro-1H-indol-5-yl)methanaminehydrochloride (2.57 g, 82%) as a yellow solid.

Intermediate 32: Preparation of(3-chloro-6-fluoro-1H-indol-5-yl)methanamine hydrochloride

Step 1: Preparation of 6-fluoro-1-triisopropylsilanyl-1H-indole

To a solution of 6-fluoro-1H-indole (5.0 g, 37.04 mmol, 1.0 eq) in dryTHF (200 mL) was added a solution of NaH (1.63 g, 40.74 mmol, 1.1 eq,60% purity) in THF (50 mL) at 0° C. After stirring for 0.5 h, TIPSCl(7.8 g, 40.74 mmol, 1.1 eq) was added. The mixture was stirred at rt for1 h, and quenched by the addition of water. The mixture was extractedwith EtOAc. The combined organic layers were dried and concentrated. Theresulting residue was purified by chromatography on silica gel column(PE/EtOAc=10/1, v/v) to afford 6-fluoro-1-triisopropylsilanyl-1H-indole(10.3 g, 87%) as a yellow oil.

Step 2: Preparation of6-fluoro-1-(triisopropylsilyl)-1H-indole-5-carbaldehyde

To a solution of 6-fluoro-1-(triisopropylsilyl)-1H-indole (2 g, 6.9mmol, 1.0 eq) in THF (30 mL) was added s-BuLi (6.3 mL, 1.3M, 1.2 eq) at−78° C. slowly. The mixture was stirred at this temperature for 1 h. DMF(1.5 g, 20.7 mmol, 3.0 eq) was added dropwise. The mixture was stirredat −78° C. for 1 h. The reaction was quenched by saturated aqueousNH₄Cl. The obtained mixture was extracted with EtOAc (50 mL×3). Theorganic layers were combined and washed with brine, dried over Na₂SO₄,filtered and concentrated. The resulting residue was purified bychromatography on silica gel column (PE/EtOAc=100/1) to give6-fluoro-1-(triisopropylsilyl)-1H-indole-5-carbaldehyde (950 mg, 57%) asa yellow oil.

Step 3: Preparation of 6-fluoro-1H-indole-5-carbaldehyde oxime

A mixture of 6-fluoro-1-(triisopropylsilyl)-1H-indole-5-carbaldehyde(780 mg, 2.45 mmol, 1.0 eq) and NH₂OH.HCl (340 mg, 4.89 mmol, 2.0 eq) inNH₃/MeOH (15% w/w, 10 mL) was stirred at rt overnight. The mixture wasconcentrated. The resulting residue was purified by chromatography onsilica gel column (PE/EtOAc=50/1) to afford6-fluoro-1H-indole-5-carbaldehyde oxime (460 mg, crude) as a yellowsolid.

Step 4: Preparation of (6-fluoro-1H-indol-5-yl)methanamine

A mixture of 6-fluoro-1H-indole-5-carbaldehyde oxime (460 mg, 1.38 mmol,1.0 eq) and Raney Ni (100 mg) in NH₃/MeOH (15% w/w, 10 mL) was stirredat rt under H₂ atmosphere (1 atm) overnight. The mixture was filteredand concentrated to afford (6-fluoro-1H-indol-5-yl)methanamine (420 mg,95%) as a gray solid, which was used in the next step without furtherpurification.

Step 5: Preparation of tert-butyl(6-fluoro-1H-indol-5-yl)methylcarbamate

To a solution of (6-fluoro-1H-indol-5-yl)methanamine (420 mg, 2.56 mmol,1.0 eq) in DCM (25 mL) was added TEA (0.43 mL, 3.07 mmol, 1.2 eq) andBoc₂O (670 mg, 3.07 mmol, 1.2 eq). The mixture was stirred at rt for 2 hand concentrated. The resulting residue was purified by chromatographyon silica gel column (PE/EtOAc=10/1, v/v) to afford tert-butyl(6-fluoro-1H-indol-5-yl)methylcarbamate (608 mg, 90%) as a yellow solid.

Step 6: Preparation of tert-butyl(3-chloro-6-fluoro-1H-indol-5-yl)methylcarbamate

To a solution of tert-butyl (6-fluoro-1H-indol-5-yl)methylcarbamate (600mg, 2.27 mmol, 1.0 eq) in DCM (20 mL) was added NCS (317 mg, 2.39 mmol,1.05 eq). The mixture was stirred at rt for 1 h and concentrated. Theresulting residue was purified by chromatography on silica gel column(PE/EtOAc=10/1, v/v) to afford tert-butyl(3-chloro-6-fluoro-1H-indol-5-yl)methylcarbamate (547 mg, 81%) as ayellow solid.

Step 7: Preparation of (3-chloro-6-fluoro-1H-indol-5-yl)methanaminehydrochloride

To a solution of tert-butyl(3-chloro-6-fluoro-1H-indol-5-yl)methylcarbamate (547 mg, 1.84 mmol, 1.0eq) in EtOAc (5 mL) was added a solution of HCl in EtOAc (10N, 10 mL).The mixture was stirred at rt for 1 h, and the precipitate was collectedby filtration to afford (3-chloro-6-fluoro-1H-indol-5-yl)methanaminehydrochloride as a yellow solid.

Example 1: Preparation of6-((4-(((3-chloro-6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2-carboxamide

To a solution ofN-(3-chloro-6-fluoro-1H-indol-5-ylmethyl)-2-(2-cyano-quinolin-6-ylmethyl)-isonicotinamide(synthesized as described in Example 3, 70 mg, 0.15 mmol, 1.0 eq) inMeOH (1.5 mL)/H₂O (0.6 mL) was added ammonium hydroxide (2.1 mL) andhydrogen peroxide (0.1 mL). The mixture was stirred at 30° C. for 3 h.The mixture was concentrated in vacuum and the residue was purified byprep-HPLC to give 6-((4-(((3-chloro-6-fluoro-1H-indol-5-yl) methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2-carboxamide (18 mg, 25%) as awhite solid. LRMS (M+H⁺) m/z calculated 488.1, found 487.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.41 (s, 1H), 9.27 (s, 1H), 8.67 (d, 1H),8.49 (d, 1H), 8.26 (s, 1H), 8.13 (d, 1H), 8.01 (d, 1H), 7.95 (s, 1H),7.82 (s, 1H), 7.78 (d, 2H), 7.67 (d, 1H), 7.51 (s, 1H), 7.46 (d, 1H),7.24 (d, 1H), 4.59 (d, 2H), 4.40 (s, 2H).

Example 2: Preparation of6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2-carboxamide

6-((4-(((6-Amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2-carboxamide(18 mg, 19%) was prepared as described for6-((4-(((3-chloro-6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2-carboxamide (Example 1) as awhite solid. LRMS (M+H⁺) m/z calculated 441.2, found 440.9.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.66-8.61 (m, 2H), 8.49 (d, 1H), 8.27 (s,1H), 8.13 (d, 1H), 8.06 (d, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.78 (s,1H), 7.62 (d, 1H), 6.13 (s, 1H), 5.71 (s, 2H), 4.38 (s, 1H), 4.35 (d,2H), 2.30 (s, 3H), 2.17 (s, 3H).

Example 3: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((2-cyanoquinolin-6-yl)methyl)isonicotinamide

To a solution of 2-(2-cyano-quinolin-6-ylmethyl)-isonicotinic acid (250mg, 0.86 mmol, 1.0 eq) in DMF (10 mL) was added6-aminomethyl-isoquinolin-1-ylamine (148.7 mg, 0.86 mmol, 1.0 eq)followed by EDCI (280.7 mg, 1.46 mmol, 1.7 eq), HOBT (174.2 mg, 1.29mmol, 1.5 eq) and TEA (0.47 mL, 3.4 mmol, 4.0 eq). The reaction mixturewas heated to 45° C. kept stirring overnight. Water was added, and themixture was extracted with DCM. The organic layer was washed with water,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby prep-HPLC to give N-((1-aminoisoquinolin-6-yl)methyl)-2-((2-cyanoquinolin-6-yl) methyl) isonicotinamide (95 mg, 25%)as a yellow solid. LRMS (M+H⁺) m/z calculated 445.2, found 445.2.

¹H NMR (DMSO-d₆, 400 MHz): δ 9.41 (t, 1H), 8.58 (d, 1H), 8.62 (d, 1H),8.15 (d, 1H), 8.09 (d, 1H), 8.01 (t, 2H), 7.91 (d, 1H), 7.89 (d, 1H),7.84 (s, 1H), 7.77 (d, 1H), 7.70 (dd, 1H), 7.56 (s, 1H), 7.41 (dd, 1H),6.85 (d, 1H), 6.76 (s, 2H), 4.62 (d, 2H), 4.44 (s, 2H).

Example 4: Preparation of6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2-carboxamide

6-((4-(((6-Amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2-carboxamide(17 mg, 23%) was prepared as described for6-((4-(((3-chloro-6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl) quinoline-2-carboxamide(Example 1) as a white solid. LRMS (M+H⁺) m/z calculated 463.2, found462.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.43 (t, 1H), 8.69 (d, 1H), 8.51 (d, 1H),8.23 (s, 1H), 8.16 (t, 2H), 8.07 (d, 1H), 7.97 (s, 1H), 7.84-7.76 (m,4H), 7.71 (d, 1H), 7.57 (s, 1H), 7.43 (d, 1H), 6.86 (d, 1H), 6.80 (s,2H), 4.63 (d, 2H), 4.42 (s, 2H).

Example 5: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-cyanoquinolin-6-yl)methyl)isonicotinamide

To a solution of 2-(3-isocyano-quinolin-6-ylmethyl)-isonicotinic acid(100 mg, 0.346 mmol, 1.0 eq) and(3-chloro-6-fluoro-1H-indol-5-yl)-methylamine (81 mg, 0.346 mmol, 1.0eq) in DMF (8 mL) were added HOBT (70 mg, 0.519 mmol, 1.5 eq), EDCI(99.5 mg, 0.519 mmol, 1.5 eq) and Et₃N (140 mg, 1.384 mmol, 4 eq). Themixture was stirred at rt for 15 h and diluted with water. The organiclayer was separated and the aqueous layer was extracted with DCM. Thecombined extracts were dried and concentrated. The residue was purifiedby prep-HPLC to giveN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-cyanoquinolin-6-yl)methyl)isonicotinamide(15 mg, 9%) as an off-white solid. LRMS (M+H⁺) m/z calculated 470.1,found 470.1.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.37 (s, 1H), 9.23 (t, 1H), 9.07 (d, 1H),8.99 (s, 1H), 8.61 (d, 1H), 8.02 (d, 1H), 7.93 (s, 1H), 7.88 (d, 1H),7.77 (s, 1H), 7.62 (d, 1H), 7.47 (d, 1H), 7.40 (d, 1H), 7.18 (d, 1H),4.54 (d, 2H), 4.37 (s, 2H).

Example 6: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-cyanoquinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-cyanoquinolin-6-yl)methyl)isonicotinamide(58 mg, 23.7%) was prepared as described forN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-cyanoquinolin-6-yl)methyl)isonicotinamide(Example 5) as an off-white solid. LRMS (M+H⁺) m/z calculated 445.2,found 444.9.

¹H NMR (DMSO-d₆, 400 MHz) δ 13.20-13.12 (m, 1H), 9.51 (t, 1H), 9.12 (d,1H), 9.06-8.99 (m, 2H), 8.69 (d, 1H), 8.50 (d, 1H), 8.07 (d, 1H), 7.99(s, 1H), 7.93 (dd, 1H), 7.83 (s, 2H), 7.73-7.71 (m, 2H), 7.66 (d, 1H),7.22 (d, 1H), 4.68 (d, 2H), 4.44 (s, 2H).

Example 7: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-cyanoquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-cyanoquinolin-6-yl)methyl)isonicotinamide(45 mg, 32.3%) was prepared as described forN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-cyanoquinolin-6-yl)methyl)isonicotinamide(Example 5) as a off white solid. LRMS (M+H⁺) m/z calculated 423.2,found 422.9. ¹H NMR (DMSO-d₆, 300 MHz) δ 9.12 (s, 1H), 9.03 (s, 1H),8.69-8.65 (m, 1H), 8.61-8.59 (m, 1H), 8.05 (dd, 1H), 7.96-7.89 (m, 2H),7.77 (s, 1H), 7.61-7.60 (m, 1H), 6.16 (d, 1H), 5.91-5.87 (m, 2H),4.38-4.33 (m, 4H), 2.31 (s, 3H), 2.18 (s, 3H).

Example 8: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((7-fluoroquinoxalin-2-yl)methyl)isonicotinamide

Step 1: Preparation of 7-fluoro-3,4-dihydro-1H-quinoxalin-2-one

To a solution of 4-fluoro-benzene-1,2-diamine (20 g, 0.159 mol, 1 eq) inDMF (150 mL) was added Et₃N (44 mL, 0.318 mol, 2 eq), followed by ethyl2-bromoacetate (29 g, 0.175 mol, 1.1 eq). The reaction mixture wasstirred at rt for 16 h, then at 80° C. for 3 h. The DMF was evaporatedby distillation. The reaction mixture was partitioned between H₂O andEtOAc. The organic layer was washed with sat. NaHCO₃, brine, and driedover Na₂SO₄. The solvent was evaporated under reduced pressure. Thedesired product was precipitated in a mixture of CH₂Cl₂ and hexane (1 to1 ratio). Filtered and the filtrate was concentrated to dryness toafford 7-fluoro-3,4-dihydro-1H-quinoxalin-2-one (22 g, 83%).

Step 2: Preparation of 7-fluoro-quinoxalin-2-ol

A mixture of 7-fluoro-3,4-dihydro-1H-quinoxalin-2-one (4.0 g, 24 mmol,1.0 eq), sodium hydroxide (1.93 g, 48 mmol, 2.0 eq) and of 3% hydrogenperoxide solution (50 mL) was refluxed for 2 h, then it was acidified byslow addition of acetic acid. The resulting mixture is cooled to roomtemperature. The precipitated solid is collected by filtration, washedwith ice-water, and dried in vacuum. The resulting residue was purifiedby column chromatography (DCM/MeOH=50:1, v/v) to afford7-fluoro-quinoxalin-2-ol (2.60 g, 69%).

Step 3: Preparation of 2-chloro-7-fluoro-quinoxaline

To the suspension of 7-fluoro-quinoxalin-2-ol (2 g, 12 mmol, 1 eq) inneat phosphorus oxychloride (10 mL) was added DMF (2 drops). The mixturewas heated to 100° C. for 3 h. Then it was cooled to room temperature.Phosphorus oxychloride was removed in vacuum, and the residue wasdissolved into EtOAc and dropped into ice water with stirring. Themixture was extracted with EtOAc for three times, the combined organiclayers were washed with saturated NaHCO₃ solution. The organic layer wasconcentrated to afford 2-chloro-7-fluoro-quinoxaline (1.7 g, 77%).

Step 4: Preparation of 7-fluoro-2-(trimethylstannyl)quinoxaline

To a solution of 2-chloro-7-fluoro-quinoxaline (2.0 g, 11 mmol, 1 eq) intoluene (50 mL) was added hexamethylditin (7.2 g, 22 mmol, 2 eq) andPd(PPh₃)₄ (635 mg, 0.55 mmol, 0.05 eq). The mixture was stirred at 90°C. for 12 h under nitrogen. The reaction mixture was concentrated, andthe resulting residue was used in next step without furtherpurification.

Step 5: Preparation of methyl2-((7-fluoroquinoxalin-2-yl)methyl)isonicotinate

To a solution of 7-fluoro-2-trimethylstannanyl-quinoxaline (3.43 g, 11mmol, 1.0 eq) in dioxane (60 mL) was added methyl2-(bromomethyl)isonicotinate (2.5 g, 11 mmol, 1.0 eq) and Pd(PPh₃)₂Cl₂(386 mg, 0.55 mmol, 0.05 eq). The mixture was stirred at 90° C. for 3 hunder nitrogen atmosphere, concentrated and purified by silica gelchromatography (PE/EtOAc=3/1, v/v) to afford methyl2-((7-fluoroquinoxalin-2-yl)methyl)isonicotinate (300 mg, 9% for 2steps) as an off-white solid.

Step 6: Preparation of N-((1-aminoisoquinolin-6-yl)methyl)-2-((7-fluoroquinoxalin-2-yl) methyl) isonicotinamide

To a solution of methyl 2-((7-fluoroquinoxalin-2-yl)methyl)isonicotinate(70 mg, 0.235 mmol, 1.0 eq) in THF (10 mL)/H₂O (2 mL) was added NaOH(11.3 mg, 0.282 mmol, 1.2 eq). The mixture was stirred at 45° C. for 2 hand was acidified to pH 5˜6 with 1N HCl solution. The mixture wasconcentrated in vacuum, and the resulting residue was used in the nextstep without further purification. To a solution of this crude productand 6-aminomethyl-isoquinolin-1-ylamine (55.2 mg, 0.235 mmol, 1.0 eq) inDMF (8 mL) were added HOBT (47.6 mg, 0.352 mmol, 1.5 eq), EDCI (67.5 mg,0.352 mmol, 1.5 eq) and Et₃N (95.1 mg, 0.940 mmol, 4 eq). The mixturewas stirred at 45° C. for 15 h, and then concentrated. The resultingresidue was purified by prep-HPLC to give N-((1-aminoisoquinolin-6-yl)methyl)-2((7-fluoroquinoxalin-2-yl) methyl) isonicotinamide (15 mg,14.6%) as a yellow solid. LRMS (M+H⁺) m/z calculated 439.2, found 438.8.¹H NMR (CD₃OD, 400 MHz) δ 8.79 (s, 1H), 8.50 (d, 1H), 7.95-7.89 (m, 2H),7.77 (s, 1H), 7.58-7.47 (m, 5H), 7.36 (d, 1H), 6.79 (d, 1H), 4.60 (s,2H), 4.51 (s, 2H)

Example 9: Preparation of2-[2-(acetylamino-methyl)-quinolin-6-ylmethyl]-N-(3-chloro-6-fluoro-1H-indol-5-ylmethyl)-isonicotinamide

To a solution of methyl2-((2-(acetamidomethyl)quinolin-6-yl)methyl)isonicotinate (100 mg, 0.287mmol, 1.0 eq) in THF (10 mL)/H₂O (2 mL) was added LiOH.H₂O (14.4 mg,0.344 mmol, 1.2 eq). The mixture was stirred at 45° C. for 2 h, and wasacidified to pH 5˜6 with 1N HCl solution. The mixture was concentratedin vacuum, and the residue was directly used without furtherpurification. To a solution of this crude product and(3-chloro-6-fluoro-1H-indol-5-yl)-methylamine (67.3 mg, 0.287 mmol, 1.0eq) in DMF (8 mL) were added HOBT (58 mg, 0.430 mmol, 1.5 eq), EDCI(82.4 mg, 0.430 mmol, 1.5 eq) and Et₃N (116 mg, 1.146 mmol, 4 eq). Themixture was stirred at 45° C. for 15 h then concentrated. The resultingresidue was purified by prep-HPLC to give2-[2-(acetylamino-methyl)-quinolin-6-ylmethyl]-N-(3-chloro-6-fluoro-1H-indol-5-ylmethyl)-isonicotinamide(15 mg, 10.2%) as a yellow solid. LRMS (M+H⁺) m/z calculated 516.2,found 515.8. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.43 (s, 1H), 9.30 (t, 1H),9.01 (s, 1H), 8.69-8.64 (m, 2H), 8.48 (d, 1H), 7.98 (d, 1H), 7.93 (s,1H), 7.84-7.78 (m, 2H), 7.71 (d, 1H), 7.56-7.51 (m, 3H), 7.45 (d, 1H),7.23 (d, 1H), 4.60-4.56 (m, 4H), 4.41 (s, 2H), 1.94 (s, 3H).

Example 10: Preparation of2-[2-(acetylamino-methyl)-quinolin-6-ylmethyl]-N-(1-amino-isoquinolin-6-ylmethyl)-isonicotinamide

2-[2-(Acetylamino-methyl)-quinolin-6-ylmethyl]-N-(1-amino-isoquinolin-6-ylmethyl)-isonicotinamide(15 mg, 10.7%) was prepared as described for2-[2-(acetylamino-methyl)-quinolin-6-ylmethyl]-N-(3-chloro-6-fluoro-1H-indol-5-ylmethyl)-isonicotinamide(Example 9) as an off white solid. LRMS (M+H⁺) m/z calculated 491.2,found 490.9. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.97 (d, 1H), 8.76 (d, 1H),8.41 (d, 1H), 8.24-8.20 (m, 2H), 8.08 (dd, 1H), 7.99 (s, 1H), 7.94-7.87(m, 3H), 7.78 (dd, 1H), 7.57 (d, 1H), 7.21 (d, 1H), 4.88 (s, 2H), 4.82(s, 2H), 4.63 (s, 2H), 2.13 (s, 3H).

Example 11: Preparation of2-[2-(acetylamino-methyl)-quinolin-6-ylmethyl]-N-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-isonicotinamide

2-[2-(Acetylamino-methyl)-quinolin-6-ylmethyl]-N-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-isonicotinamide(10 mg, 7.46%) was prepared as described for2-[2-(acetylamino-methyl)-quinolin-6-ylmethyl]-N-(3-chloro-6-fluoro-1H-indol-5-ylmethyl)-isonicotinamide(Example 9) as a yellow solid. LRMS (M+H⁺) m/z calculated 469.2, found469.2.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.48 (m, 1H), 8.13 (d, 1H), 7.82 (d, 1H),7.66 (s, 1H), 7.59-7.54 (m, 2H), 7.48 (dd, 1H), 7.35 (d, 1H), 6.18 (s,1H), 4.53 (s, 2H), 4.37 (s, 2H), 4.26 (s, 2H), 2.27 (s, 3H), 2.13 (s,3H), 1.96 (s, 3H).

Example 12: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide

Step 1: Preparation of 6-methanesulfonyl-quinoline

A mixture of 6-bromo-quinoline (20.7 g, 0.1 mol, 1 eq), sodiummethanesulphinate (12.2 g, 0.12 mol, 1.2 eq), copper iodide (1.9 g, 0.01mol, 0.1 eq), L-proline sodium salt (2.74 g, 0.02 mol, 0.2 eq) in 200 mLof DMSO was heated to 110° C. under nitrogen for 15 h. The cooledmixture was partitioned between ethyl acetate and water. The organiclayer was separated, and the aqueous layer was extracted with ethylacetate twice. The combined organic layers were washed with brine, driedover MgSO₄, and concentrated in vacuum. The resulting residue waspurified by silica gel column (EtOAc/PE=1/2, v/v) to give6-methanesulfonyl-quinoline (13.5 g, 65%) as a yellow solid.

Step 2: Preparation of 3-bromo-6-methanesulfonyl-quinoline

To a mixture of 6-methanesulfonyl-quinoline (6.0 g, 29.0 mmol, 1 eq) andpyridine (4.7 mL, 58.0 mmol, 2 eq) in CCl₄ (250 mL) was added Br₂ (0.9mL, 34.8 mmol, 1.2 eq) drop wise. The mixture was heated to reflux for 2h before being cooled to room temperature. The liquid in the flask wasdecanted and washed with saturated aqueous NaHCO₃ and water. The darksolid on the bottom of the flask was partitioned between aqueous NaHCO₃and dichloromethane. The combined organic layers were washed with wateragain and dried before being evaporated to dryness in vacuum. The crudeproduct was purified by silica gel column (EtOAc/PE=1/10, v/v) to give3-bromo-6-methanesulfonyl-quinoline (6.2 g, 75%) as a yellow solid.

Step 3: Preparation of 6-methanesulfonyl-3-vinyl-quinoline

To a solution of 3-bromo-6-methanesulfonyl-quinoline (2.9 g, 10.2 mmol,1 eq) and vinylboronic acid pinacol cyclic ester (2.1 g, 12.2 mmol, 1.2eq) in dioxane (50 mL) and water (10 mL) was added Na₂CO₃ (3.24 g, 30.6mmol, 3 eq) and Pd(dppf)Cl₂.CH₂Cl₂ (833 mg, 1.02 mmol, 0.1 eq). Themixture was stirred at 95° C. for 3 h. After cooling to rt, the solventwas removed in vacuum. The residue was purified by flash chromatographyon a silica gel column (EtOAc/PE=1/10, v/v) to afford6-methanesulfonyl-3-vinyl-quinoline as a yellow solid (2.1 g, 88%).

Step 4: Preparation of 6-methanesulfonyl-quinoline-3-carbaldehyde

A 3-neck round-bottom flask was charged with6-methanesulfonyl-3-vinyl-quinoline (2.1 g, 9.0 mmol, 1 eq) anddichloromethane (40 mL) and cooled to −78° C. Ozone was bubbled into thereaction mixture until blue color persisted (30 min). The reactionmixture was sparged with oxygen until blue color faded and quenched withmethyl sulfide (6 mL). The mixture was stirred at rt for 1 h, thenconcentrated and purified by flash column chromatography (EtOAc/PE=1/8,v/v) to give 6-methanesulfonyl-quinoline-3-carbaldehyde (1.0 g, 47%) asa white solid.

Step 5: Preparation of (6-methanesulfonyl-quinolin-3-yl)-methanol

To a solution of 6-methanesulfonyl-quinoline-3-carbaldehyde (1.0 g, 4.25mmol, 1 eq) in dry MeOH (20 mL) was added NaBH₄ (162 mg, 4.25 mmol, 1eq) at 0° C. The mixture was stirred at the same temperature for 10 min.The reaction was quenched by the addition of water. The mixture wasextracted with EtOAc. The combined extracts were dried and concentrated.The residue was purified by chromatography on a silica gel column(EtOAc/PE=1/2, v/v) to afford (6-methanesulfonyl-quinolin-3-yl)-methanolas a yellow solid (290 mg, 29%).

Step 6: Preparation of 3-chloromethyl-6-methanesulfonyl-quinoline

To (6-methanesulfonyl-quinolin-3-yl)-methanol (290 mg, 1.22 mmol, 1.0eq) was added SOCl₂ (5 mL) and the mixture was stirred at rt for 2 h.The volatiles were then removed at 40° C. under vacuum, and the residuewas dissolved in DCM. The mixture was washed with saturated aq. NaHCO₃,dried and concentrated to give3-chloromethyl-6-methanesulfonyl-quinoline (310 mg, 99%) as a yellowsolid.

Step 7: Preparation of methyl2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinate

To a solution of 3-chloromethyl-6-methanesulfonyl-quinoline (310 mg,2.61 mmol, 1.0 eq) in dioxane (20 mL) was added methyl2-(trimethylstannyl)isonicotinate (864 mg, 2.87 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (183 mg, 0.26 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, concentrated and purified bysilica gel chromatography (DCM/MeOH=100/1, v/v) to afford methyl2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinate (290 mg, 67%)as a yellow solid.

Step 8: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide

To a solution of methyl2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinate (85 mg, 0.24mmol, 1.0 eq) in THF (3 mL)/H₂O (2 mL) was added LiOH.H₂O (15 mg, 0.36mmol, 1.5 eq). The mixture was stirred at 40° C. for 1 h and wasacidified to pH 5 with 1N HCl solution. The mixture was concentrated invacuum and the residue was directly used without further purification.To a solution of the above crude product and(3-chloro-6-fluoro-1H-indol-5-yl)-methylamine hydrochloride (68 mg, 0.29mmol, 1.2 eq) in DMF (5 mL) was added HATU (137 mg, 0.36 mmol, 1.5 eq)and Et₃N (97 mg, 0.96 mmol, 4 eq). The mixture was stirred at rt for 1 hand concentrated. The residue was purified by prep-HPLC to giveN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide(53 mg, 43% for 2 steps) as an off-white solid. LRMS (M+H⁺) m/zcalculated 523.1, found 522.8. ¹H NMR (DMSO-d6, 400 MHz) δ 11.90 (s,1H), 9.29 (s, 1H), 9.10 (s, 1H), 8.66 (d, 1H), 8.63 (s, 1H), 8.50 (s,1H), 8.22 (d, 1H), 8.14 (d, 1H), 7.85 (s, 1H), 7.68 (d, 1H), 7.52 (s,1H), 7.47 (d, 1H), 4.61 (d, 2H), 4.46 (s, 2H), 3.37 (s, 3H).

Example 13: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide(56 mg, 46% for 2 steps) was prepared as described forN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide(Example 12) as an off-white solid. LRMS (M+H⁺) m/z calculated 498.2,found 497.9.

¹H NMR (CD₃OD, 400 MHz) δ 8.85 (s, 1H), 8.51 (d, 1H), 8.37 (s, 1H), 8.21(s, 1H), 7.99 (s, 1H), 7.89 (d, 1H), 7.71 (s, 1H), 7.55 (s, 1H), 7.53(d, 1H), 7.45 (s, 1H), 7.32 (d, 1H), 6.74 (d, 1H), 4.56 (s, 2H), 4.32(s, 2H), 3.07 (s, 3H).

Example 14: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide(35 mg, 32% for 2 steps) was prepared as described forN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide(Example 12) as an off-white solid. LRMS (M+H⁺) m/z calculated 476.2,found 476.0.

¹H NMR (CD₃OD, 400 MHz) δ 8.91 (d, 1H), 8.51 (d, 1H), 8.47 (s, 1H), 8.31(s, 1H), 8.09 (d, 1H), 8.08 (d, 1H), 7.67 (s, 1H), 7.51 (d, 1H), 6.20(s, 1H), 4.40 (s, 2H), 4.37 (s, 2H), 3.11 (s, 3H), 2.29 (s, 3H), 2.16(s, 3H).

Example 15: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of methyl 4-amino-3-iodobenzoate

To a solution of methyl 4-aminobenzoate (20 g, 0.132 mol, 1 eq) in AcOH(500 mL) was added a solution of ICl (23.6 g, 0.146 mol, 1.1 eq) in AcOH(500 mL) at 0° C. The mixture was stirred at rt for 2 h. AcOH wasevaporated under reduced pressure. The residue was diluted with DCM andwashed with sat. NaHCO₃. The aqueous layer was extracted with DCM andthe combined extracts were dried and concentrated. The residue waspurified by chromatography on a silica gel column (EtOAc/PE=1/15, v/v)to give methyl 4-amino-3-iodobenzoate (27.4 g, 75%) as an off-whitesolid.

Step 2: Preparation of methyl 8-iodo-3-methylquinoline-6-carboxylate

A mixture of methyl 4-amino-3-iodobenzoate (26 g, 93.5 mmmol),2-methyl-propenal (24.5 g, 0.28 mol, 3 eq) and 6N HCl (95 mL) was heatedto reflux for 24 h. Then the mixture was cooled and adjusted to pH˜5-6using NaHCO₃ (aq). The mixture was extracted with DCM. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered thenconcentrated and purified by column chromatography (EtOAc/PE=1/20, v/v)to give methyl 8-iodo-3-methylquinoline-6-carboxylate (10.2 g, 33%) as ayellow solid.

Step 3: Preparation of (8-iodo-3-methyl-quinolin-6-yl)-methanol

To a solution of methyl 8-iodo-3-methylquinoline-6-carboxylate (7.5 g,22.9 mmol, 1 eq) was added LiAlH(t-BuO)₃ (14.6 g, 57.3 mmol, 2.5 eq).The resulting mixture was stirred at 40° C. for 12 h and then quenchedby the addition of water. The mixture was extracted with EtOAc. Thecombined extracts were dried and concentrated. The residue was purifiedby silica gel chromatography (PE/EtOAc=2/1, v/v) to afford(8-iodo-3-methyl-quinolin-6-yl)-methanol (6.5 g, 95%) as a yellow solid.

Step 4: Preparation of(8-methanesulfonyl-3-methyl-quinolin-6-yl)-methanol

A mixture of (8-iodo-3-methyl-quinolin-6-yl)-methanol (6.5 g, 21.7 mmol,1 eq), sodium methanesulphinate (2.66 g, 26.1 mmol, 1.2 eq), copperiodide (412 mg, 2.17 mol, 0.1 eq), L-proline sodium salt (594 mg, 4.34mol, 0.2 eq) in 100 mL of DMSO was heated to 110° C. under nitrogen for15 h. The cooled mixture was partitioned between ethyl acetate andwater. The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate twice. The combined organic layers werewashed with brine, dried over MgSO₄, and concentrated in vacuum. Theresidue was purified by silica gel column (EtOAc/PE=1/2, v/v) to give(8-methanesulfonyl-3-methyl-quinolin-6-yl)-methanol (3.3 g, 60%) as ayellow solid.

Step 5: Preparation of6-chloromethyl-8-methanesulfonyl-3-methyl-quinoline

To (8-methanesulfonyl-3-methyl-quinolin-6-yl)-methanol (3.3 g, 13.1mmol, 1.0 eq) was added SOCl₂ (50 mL) and the mixture was stirred at rtfor 1 h. The volatiles were then removed under vacuum and the residuewas dissolved in DCM. The mixture was washed with saturated aq. NaHCO₃,dried and concentrated to give6-chloromethyl-8-methanesulfonyl-3-methyl-quinoline (3.4 g, 96%) as ayellow solid.

Step 6: Preparation of methyl2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinate

To a solution of 6-chloromethyl-8-methanesulfonyl-3-methyl-quinoline(3.0 g, 11.1 mmol, 1.0 eq) in dioxane (60 mL) was added methyl2-(trimethylstannyl)isonicotinate (3.70 g, 12.3 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (779 mg, 1.11 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, concentrated and purified bysilica gel chromatography (DCM/MeOH=100/1, v/v) to afford methyl2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinate (2.26g, 55%) as a yellow solid.

Step 7: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

To a solution of methyl2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinate (120mg, 0.32 mmol, 1.0 eq) in THF (3 mL)/H₂O (2 mL) was added LiOH.H₂O(26.88 mg, 0.64 mmol, 2.0 eq). The mixture was stirred at 40° C. for 1 hand was acidified to pH 5 with 1N HCl solution. The mixture wasconcentrated in vacuo and the residue was directly used without furtherpurification. To a solution of the above crude product and5-aminomethyl-4,6-dimethyl-pyridin-2-ylamine (96.64 mg, 0.64 mmol, 2.0eq) in DMF (5 mL) was added HOBT (64.8 mg, 0.48 mmol, 1.5 eq), EDCI(104.45 mg, 0.54 mmol, 1.7 eq) and Et₃N (0.17 mL, 1.28 mmol, 4 eq). Themixture was stirred at rt for overnight and diluted with water. Theorganic layer was separated and the aqueous layer was extracted withDCM. The combined extracts were dried and concentrated. The residue waspurified by prep-HPLC to giveN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(30 mg, 18% for 2 steps) as an off-white solid. LRMS (M+H⁺) m/zcalculated 490.2, found 490.0. ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.93 (s,1H), 8.67 (d, 2H), 8.27 (s, 2H), 8.16 (s, 1H), 7.82 (s, 1H), 7.63 (d,1H), 6.13 (s, 1H), 5.70 (s, 2H), 4.44 (s, 2H), 4.35 (s, 2H), 3.58 (s,3H), 2.52 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H).

Example 16: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(60 mg, 35% for 2 steps) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(Example 15) as yellow solid. LRMS (M+H⁺) m/z calculated 512.2, found512.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.85 (s, 1H), 8.64 (d, 1H), 8.31 (s, 1H),8.11 (s, 1H), 8.05 (d, 2H), 7.81 (s, 1H), 7.69 (d, 2H), 7.60 (s, 1H),7.47 (d, 1H), 6.91 (d, 1H), 4.69 (s, 2H), 4.45 (s, 2H), 3.52 (s, 3H),2.52 (s, 3H).

Example 17: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(30 mg, 17% for 2 steps) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(Example 15) as yellow solid. LRMS (M+H⁺) m/z calculated 537.1, found537.1.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.40 (s, 1H), 9.26 (t, 1H), 8.93 (d, 1H),8.67 (d, 1H), 8.28 (d, 2H), 8.16 (s, 1H), 7.86 (s, 1H), 7.68 (d, 1H),7.51 (d, 1H), 7.46 (d, 1H), 7.24 (d, 1H), 4.60 (d, 2H), 4.45 (s, 2H),3.57 (s, 3H), 2.50 (s, 3H).

Example 18: Preparation ofN-((6-fluoro-1H-indol-5-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((6-fluoro-1H-indol-5-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(40 mg, 28% for 2 steps) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(Example 15) as an off-white solid. LRMS (M+H⁺) m/z calculated 503.2,found 503.0. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.12 (s, 1H), 9.24 (t, 1H),8.92 (d, 1H), 8.68 (d, 1H), 8.28 (d, 2H), 8.16 (s, 1H), 7.89 (s, 1H),7.70 (d, 1H), 7.52 (d, 1H), 7.32 (s, 1H), 7.19 (d, 1H), 6.41 (d, 1H),4.59 (d, 2H), 4.46 (s, 1H), 3.58 (s, 3H), 2.51 (s, 3H).

Example 19: Preparation ofN-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(55 mg, 38%) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(Example 15) as a white solid. LRMS (M+H⁺) m/z calculated 520.1, found519.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.35 (t, 1H), 8.92 (s, 1H), 8.66 (d, 1H),8.26-8.32 (m, 3H), 8.16 (s, 1H), 7.88 (s, 1H), 7.85 (s, 1H), 7.65-7.68(m, 2H), 4.59 (d, 2H), 4.45 (s, 2H), 3.56 (s, 3H), 2.51 (s, 3H).

Example 20: Preparation ofN-((5-chloro-1H-indazol-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((5-chloro-1H-indazol-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(30 mg, 21%) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(Example 15) as a yellow solid. LRMS (M+H⁺) m/z calculated 520.1, found519.8. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.41 (t, 1H), 8.92 (s, 1H), 8.66 (d,1H), 8.27 (d, 2H), 8.15 (s, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.65 (d,1H), 7.53 (d, 1H), 7.33 (d, 1H), 4.79 (d, 2H), 4.45 (s, 2H), 3.56 (s,3H), 2.51 (s, 3H).

Example 21: Preparation ofN-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(40 mg, 27%) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(Example 15) as a white solid. LRMS (M+H⁺) m/z calculated 537.1, found536.7.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.60 (s, 1H), 9.26 (t, 1H), 8.92 (s, 1H),8.66 (d, 1H), 8.27 (d, 2H), 8.16 (s, 1H), 7.85 (s, 1H), 7.65 (d, 1H),7.52 (d, 1H), 7.12-7.21 (m, 2H), 4.58 (d, 2H), 4.45 (s, 2H), 3.57 (s,3H), 2.51 (s, 3H).

Example 22: Preparation ofN-(6-Amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(5-chloro-1-oxo-1H-isoquinolin-2-ylmethyl)-isonicotinamide

Step 1: Preparation of methyl 2-chlorophenethylcarbamate

To a solution of 2-(2-chloro-phenyl)-ethylamine (10 g, 64 mmol, 1.0 eq)in DCM (150 mL) was added TEA (12.9 g, 128 mmol, 2.0 eq). The mixturewas stirred at 0° C., and methyl chloroformate (9.07 g, 96 mmol, 1.5 eq)was added under nitrogen atmosphere. The mixture was allowed to warm tort and stirred for 1 h, concentrated and purified by silica gelchromatography (PE/EtOAc=5/1, v/v) to afford methyl2-chlorophenethylcarbamate (9.0 g, 66%) as a colorless oil.

Step 2: Preparation of 5-chloro-3,4-dihydro-2H-isoquinolin-1-one

Trifluoromethanesulfonic acid (170 mL, 2.2 mol, 50 eq) was added toN-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(5-chloro-1-oxo-1H-isoquinolin-2-ylmethyl)-isonicotinamide(9.0 g, 44.2 mmol, 1.0 eq) at 0° C. The mixture was stirred at 70° C.for 24 h under nitrogen. Then the mixture was poured into ice-water toafford 5-chloro-3,4-dihydro-2H-isoquinolin-1-one (5.1 g, 67%) as ayellow oil.

Step 3: Preparation of 5-chloro-2H-isoquinolin-1-one

To a solution of 5-chloro-3,4-dihydro-2H-isoquinolin-1-one (5.1 g, 28mmol, 1.0 eq) in dioxane (150 mL) was added DDQ (22 g, 70 mmol, 3.4 eq).The mixture was stirred at 100° C. for 72 h. The solvent was removed andEtOAc was added. Then washed with 10% NaOH, the organic layer wasconcentrated, and purified by silica gel chromatography (PE/EtOAc=3/1,v/v) to afford 5-chloro-2H-isoquinolin-1-one (1.3 g, 25%) as an orangeoil.

Step 4: Preparation of methyl2-((5-chloro-1-oxoisoquinolin-2(1H)-yl)methyl)isonicotinate

To a solution of 5-chloro-2H-isoquinolin-1-one (470 mg, 2.6 mmol, 1.0eq) in DMF (10 mL) was added K₂CO₃ (723 mg, 5.2 mmol, 2.0 eq) and methyl2-(chloromethyl)isonicotinate (722 mg, 3.9 mmol, 1.5 eq). The mixturewas stirred at 30° C. for 4 h. The solvent was removed and purified bysilica gel chromatography (PE/EtOAc=3/1, v/v) to afford methyl2-((5-chloro-1-oxoisoquinolin-2(1H)-yl)methyl)isonicotinate (710 mg,83%) as a yellow solid.

Step 5: Preparation ofN-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(5-chloro-1-oxo-1H-isoquinolin-2-ylmethyl)-isonicotinamide

To a solution of methyl2-((5-chloro-1-oxoisoquinolin-2(1H)-yl)methyl)isonicotinate (210 mg,0.54 mmol, 1.0 eq) in THF (5 mL)/H₂O (5 mL) was added NaOH (43 mg, 1.08mmol, 2.0 eq). The mixture was stirred at 40° C. for 1 h and wasacidified to pH 5 with 1N HCl solution. The mixture was concentrated invacuum and the residue was directly used without further purification.To a solution of the above crude product and4-aminomethyl-3,5-dimethyl-phenylamine (122 mg, 0.81 mmol, 1.5 eq) inDMF (8 mL) was added HATU (230 mg, 0.6 mmol, 1.2 eq) and Et₃N (0.3 mL,1.62 mmol, 3 eq). The mixture was stirred at rt for overnight,concentrated and purified by flash chromatography on a silica gel column(DCM/MeOH=10/1, v/v) to giveN-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(5-chloro-1-oxo-1H-isoquinolin-2-ylmethyl)-isonicotinamide(31 mg, 13% for 2 steps) as a white solid. LRMS (M+H⁺) m/z calculated448.2, found 448.0. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.71 (m, 1H), 8.56-8.57(d, 1H), 8.16-8.18 (d, 1H), 7.88-7.90 (d, 1H), 7.74-7.76 (d, 1H), 7.70(s, 1H), 7.64-7.65 (d, 1H), 7.48-7.52 (t, 1H), 6.81-6.83 (d, 1H), 6.14(s, 1H), 5.80 (m, 2H), 5.34 (s, 2H), 4.33-4.34 (d, 2H), 2.30 (s, 3H),2.17 (s, 3H).

Example 23: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6-chloro-1-oxoisoquinolin-2(1H)-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6-chloro-1-oxoisoquinolin-2(1H)-yl)methyl)isonicotinamide(45 mg, 33%) was prepared as described forN-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(5-chloro-1-oxo-1H-isoquinolin-2-ylmethyl)-isonicotinamide(Example 22) as a white solid. LRMS (M+H⁺) m/z calculated 448.2, found447.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.71 (s, 1H), 8.58 (d, 1H), 8.17 (d, 1H),7.83 (s, 1H), 7.68-7.65 (m, 3H), 7.54 (dd, 1H), 6.67 (d, 1H), 6.15 (s,1H), 5.74 (br, 2H), 4.35 (d, 2H), 2.31 (s, 3H), 2.17 (s, 3H).

Example 24: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-1H-indol-5-yl)methyl)isonicotinamide

Step 1: Preparation of methyl 3-chloro-1H-indole-5-carboxylate

To a solution of methyl 1H-indole-5-carboxylate (10.0 g, 57.1 mmol, 1.0eq) in MeOH was added NCS (8.4 g, 62.8 mmol, 1.1 eq). The mixture wasstirred at rt for 3 h. MeOH was removed by evaporation and the residuewas re-dissolved in EtOAc. The mixture was washed with brine twice. Theorganic layer was dried and concentrated to give methyl3-chloro-1H-indole-5-carboxylate (quant) as a yellow solid.

Step 2: Preparation of 1-tert-butyl 5-methyl3-chloro-1H-indole-1,5-dicarboxylate

To a solution of methyl 3-chloro-1H-indole-5-carboxylate (11.9 g, 57.1mmol, 1.0 eq) in MeOH was added Boc₂O (18.7 g, 86.7 mmol, 1.5 eq) andDMAP (348 mg, 2.86 mmol, 0.05 eq). The mixture was stirred at rt for 2h. The mixture was concentrated and purified by chromatography on asilica gel column (EtOAc/PE=1/10, v/v) to give 1-tert-butyl 5-methyl3-chloro-1H-indole-1,5-dicarboxylate (13.4 g, 76%) as an off-whitesolid.

Step 3: Preparation of tert-butyl3-chloro-5-(hydroxymethyl)-1H-indole-1-carboxylate

To a solution of 1-tert-butyl 5-methyl3-chloro-1H-indole-1,5-dicarboxylate (7.0 g, 22.6 mmol, 1 eq) in THF(100 mL) was added LiAlH(t-BuO)₃ (14.4 g, 56.6 mmol, 2.5 eq). Theresulting mixture was stirred at 60° C. for 12 h and then quenched bythe addition of water. The mixture was extracted with EtOAc. Thecombined extracts were dried and concentrated. The residue was purifiedby silica gel chromatography (PE/EtOAc=2/1, v/v) to afford tert-butyl3-chloro-5-(hydroxymethyl)-1H-indole-1-carboxylate (4.3 g, 68%) as awhite solid.

Step 4: Preparation of tert-butyl3-chloro-5-(chloromethyl)-1H-indole-1-carboxylate

To a solution of tert-butyl3-chloro-5-(hydroxymethyl)-1H-indole-1-carboxylate (1.5 g, 5.34 mmol, 1eq) in dry DCM (30 mL) was added Et₃N (1.5 mL, 10.68 mmol, 2 eq) andMsCl (0.62 mL, 8.01 mmol, 1.5 eq). The resulting mixture was stirred atrt for 24 h and then quenched by the addition of water. The mixture wasextracted with DCM. The combined extracts were dried and concentrated.The residue was purified by silica gel chromatography (PE/EtOAc=20/1,v/v) to afford tert-butyl3-chloro-5-(chloromethyl)-1H-indole-1-carboxylate (1.17 g, 73%) as awhite solid.

Step 5: Preparation of tert-butyl3-chloro-5-((4-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-indole-1-carboxylate

To a solution of tert-butyl3-chloro-5-(chloromethyl)-1H-indole-1-carboxylate (1.1 g, 3.68 mmol, 1.0eq) in dioxane (20 mL) was added methyl2-(trimethylstannyl)isonicotinate (1.22 g, 4.05 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (260 mg, 0.37 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, concentrated and purified bysilica gel chromatography (PE/EtOAc=20/1, v/v) to afford tert-butyl3-chloro-5-((4-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-indole-1-carboxylate(690 mg, 47%) as an off-white solid.

Step 6: Preparation of 2-(3-chloro-1H-indol-5-ylmethyl)-isonicotinicacid

To a solution of tert-butyl3-chloro-5-((4-(methoxycarbonyl)pyridin-2-yl)methyl)-1H-indole-1-carboxylate(690 mg, 1.72 mmol, 1.0 eq) in DCM (3 mL) was added TFA (5 mL). Themixture was stirred at rt for 2 h. Then the mixture was concentrated andthe residue was re-dissolved in DCM and washed with sat. NaHCO₃ aq. Theorganic layer was concentrated. The residue was dissolved in THF/H₂O (5mL, v/v=1:1). To the mixture was added NaOH. The mixture was stirred atrt for 0.5 h. Then the mixture was acidified to pH 5 with 1N HCl. Themixture was extracted with EtOAc. The combined organic layers were driedand concentrated to give 2-(3-chloro-1H-indol-5-ylmethyl)-isonicotinicacid (220 mg, 45%) as a yellow solid.

Step 7: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-1H-indol-5-yl)methyl)isonicotinamide

To a solution of 2-(3-chloro-1H-indol-5-ylmethyl)-isonicotinic acid (100mg, 0.35 mmol, 1 eq) and 4-aminomethyl-3,5-dimethyl-phenylamine (117 mg,0.52 mmol, 1.5 eq) in DMF (5 mL) was added HATU (160 mg, 0.42 mmol, 1.2eq) and Et₃N (140 mg, 1.40 mmol, 4 eq). The mixture was stirred at rtfor 1 h, concentrated and purified by prep-HPLC to giveN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-1H-indol-5-yl)methyl)isonicotinamide (35 mg, 24%) as an off-white solid. LRMS (M+H⁺)m/z calculated 420.2, found 419.8.

¹H NMR (CD₃OD, 400 MHz) δ 8.54 (d, 1H), 7.61 (s, 1H), 7.54 (dd, 1H),7.38 (s, 1H), 7.29 (d, 1H), 7.20 (s, 1H), 7.06 (dd, 1H), 6.28 (s, 1H),4.45 (s, 2H), 4.25 (d, 2H), 2.36 (s, 3H), 2.22 (s, 3H).

Example 25: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-1H-indol-5-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-1H-indol-5-yl)methyl)isonicotinamide(25 mg, 16%) was prepared as described in Example 24, Step 7 as a whitesolid. LRMS (M+H⁺) m/z calculated 400.2, found 399.9. ¹H NMR (CD₃OD, 400MHz) δ 8.53 (d, 1H), 7.59 (s, 1H), 7.52 (d, 1H), 7.37 (s, 1H), 7.23 (d,1H), 6.97 (d, 1H), 6.95 (s, 1H), 6.27 (s, 1H), 4.45 (s, 2H), 4.24 (d,2H), 2.35 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H).

Example 26: Preparation ofN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of 5-aminomethyl-6-methyl-pyridin-2-ylaminehydrochloride

The mixture of 6-amino-2-methyl-nicotinonitrile (2 g, 15.0 mmol, 1 eq),Pd/C (10%, 500 mg), and con.HCl (3 mL) in a solution of EtOH/MeOH (10mL/10 mL) was stirred at rt under H₂ (50 psi) for overnight. Thereaction mixture was filtered, and the filtrate was concentrated to givecrude 5-aminomethyl-6-methyl-pyridin-2-ylamine hydrochloride (3.5 g) asa yellow solid. LRMS (M+H⁺) m/z calculated 138, found 138.

Step 2: Preparation of tert-butyl(6-amino-2-methylpyridin-3-yl)methylcarbamate

The mixture of 5-aminomethyl-6-methyl-pyridin-2-ylamine hydrochloride(3.5 g, crude) in DCM (50 mL) was added TEA (4.5 g, 45.0 mmol, 3 eq)followed by Boc₂O (4.9 g, 22.5 mmol, 1.5 eq). The reaction mixture wasstirred at rt overnight. The reaction mixture was concentrated. Theresidue was purified by column chromatography on a silica gel(DCM/MeOH=20/1, v/v) to give tert-butyl(6-amino-2-methylpyridin-3-yl)methylcarbamate (3 g) as a white solid.LRMS (M+H⁺) m/z calculated 238, found 238.

Step 3: Preparation of tert-butyl(6-amino-5-bromo-2-methylpyridin-3-yl)methylcarbamate

To the solution of tert-butyl(6-amino-2-methylpyridin-3-yl)methylcarbamate (3 g, 13.7 mmol, 1 eq) inDCM (30 mL) was added NBS (2.5 g, 13.9 mmol, 1.1 eq). The resultingmixture was concentrated. The residue was purified by columnchromatography on a silica gel (PE/EtOAc=10/1 to EtOAc, v/v) to givetert-butyl (6-amino-5-bromo-2-methylpyridin-3-yl)methylcarbamate (2 g,50%) as a white solid. LRMS (M+H⁺) m/z calculated 316,318, found316,318.

Step 4: Preparation of tert-butyl(6-amino-5-cyano-2-methylpyridin-3-yl)methylcarbamate

The mixture of tert-butyl(6-amino-5-bromo-2-methylpyridin-3-yl)methylcarbamate (500 mg, 1.58mmol, 1 eq), Zn(CN)₂ (185 mg, 1.58 mmol, 1.0 eq) and Pd(PPh₃)₄ (182 mg,0.16 mmol, 0.1 eq) in DMF (20 mL) was heated to 95° C. and kept stirringfor 3 h. Then it was cooled to rt, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography on asilica gel (PE/EtOAc=2/1, v/v) to give tert-butyl(6-amino-5-cyano-2-methylpyridin-3-yl)methylcarbamate (300 mg, 72%) as awhite solid. LRMS (M+H⁺) m/z calculated 263, found 263.

Step 5: Preparation of 2-amino-5-aminomethyl-6-methyl-nicotinonitrilehydrochloride

To the mixture of tert-butyl(6-amino-5-cyano-2-methylpyridin-3-yl)methylcarbamate (1.2 g, 4.6 mmol,1 eq) in EtOAc (10 mL) was added 10 mL of 6N HCl in EtOAc and keptstirring for 2 h. The reaction mixture was filtered, and the filter cakewas washed with EtOAc to give2-amino-5-aminomethyl-6-methyl-nicotinonitrile hydrochloride (600 mg,67%) as a white solid. LRMS (M+H⁺) m/z calculated 163, found 163.

Step 6: Preparation ofN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

To a solution of 2-(3-chloro-quinolin-6-ylmethyl)-isonicotinic acid (80mg, 0.27 mmol, 1 eq) in DMF (10 mL) was added2-amino-5-aminomethyl-6-methyl-nicotinonitrile hydrochloride (54 mg,0.27 mmol, 1 eq) followed by EDCI (78 mg, 0.41 mmol, 1.5 eq), HOBT (55mg, 0.41 mmol, 1.5 eq) and TEA (82 mg, 0.81 mmol, 3.0 eq). The reactionmixture was heated to 45° C. kept stirring for overnight. Water wasadded, and the mixture was extracted with DCM. The organic layer waswashed with water, dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by prep-HPLC to giveN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(60 mg, 50%) as a white solid. LRMS (M+H⁺) m/z calculated 443.1, found442.8.

¹H NMR (DMSO-d₆, 400 MHz): δ 9.04 (t, 1H), 8.83 (d, 1H), 8.64 (d, 1H),8.53 (s, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.74 (d, 1H),7.68 (s, 1H), 7.63 (s, 1H), 6.78 (s, 2H), 4.37 (s, 2H), 4.31 (d, 2H),2.36 (s, 3H).

Example 27: Preparation of2-amino-5-((2-((3-chloroquinolin-6-yl)methyl)isonicotinamido)methyl)-6-methylnicotinamide

To a solution ofN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(80 mg, 0.18 mmol, 1 eq) in DMF (5 mL) was added K₂CO₃ (50 mg, 0.36mmol, 2.0 eq) followed by 30% of H₂O₂ (2 mL). The reaction mixture washeated to 50° C. kept stirring for 3 h. The reaction mixture wasconcentrated. The residue was purified by prep-HPLC to give2-amino-5-((2-((3-chloroquinolin-6-yl)methyl)isonicotinamido)methyl)-6-methylnicotinamide(45 mg, 54%) as a white solid. LRMS (M+H⁺) m/z calculated 461.1, found461.1.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.91 (t, 1H), 8.83 (d, 1H), 8.63 (d, 1H),8.53 (d, 1H), 7.98 (d, 1H), 7.86 (s, 3H), 7.78 (s, 1H), 7.74 (d, 1H),7.64 (d, 1H), 7.13-7.21 (m, 3H), 4.36 (s, 2H), 4.32 (d, 2H), 2.31 (s,3H).

Example 28: Preparation ofN-((6-amino-5-chloro-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of 6-amino-5-chloro-2-methyl-nicotinonitrile

The mixture of 6-amino-2-methyl-nicotinonitrile (500 mg, 3.76 mmol, 1eq) and NCS (1 g, 7.52 mmol, 2 eq) in AcOH (10 mL) was heated to 60° C.and kept stirring for 2 h. The reaction mixture was concentrated. Theresidue was purified by column chromatography on a silica gel(PE/EtOAc=10/1 to EtOAcv/v) to give6-amino-5-chloro-2-methyl-nicotinonitrile (400 mg, 64%) as a whitesolid. LRMS (M+H⁺) m/z calculated 168, found 168.

Step 2: Preparation of 5-aminomethyl-3-chloro-6-methyl-pyridin-2-ylaminehydrochloride

The mixture of 6-amino-5-chloro-2-methyl-nicotinonitrile (400 mg, 2.4mmol, 1 eq), Rany Ni (400 mg) and conc. HCl (1 mL) in EtOH/MeOH (10mL/10 mL) was stirred under H₂ (1 atm) at rt for overnight. The reactionmixture was filtered, and the filtrate was concentrated to give crude5-aminomethyl-3-chloro-6-methyl-pyridin-2-ylamine hydrochloride (1 g) asa yellow solid. LRMS (M+H⁺) m/z calculated 172, found 172.

Step 3: Preparation ofN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-5-chloro-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(15 mg, 12%) was prepared as described forN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(Example 26) as a white solid. LRMS (M+H⁺) m/z calculated 452.1, found451.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.03 (t, 1H), 8.83 (d, 1H), 8.63 (d, 1H),8.52 (d, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.72-7.76 (m, 2H), 7.62 (d,1H), 7.41 (s, 1H), 6.11 (s, 2H), 4.36 (s, 2H), 4.29 (d, 2H), 2.29 (s,3H).

Example 29: Preparation ofN-((6-amino-4-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-4-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(25 mg, 22%) was prepared as described forN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(Example 26) as a white solid. LRMS (M+H⁺) m/z calculated 418.1, found417.8.

¹H NMR (DMSO-d₆, 300 MHz) δ 8.93 (t, 1H), 8.83 (d, 1H), 8.62 (d, 1H),8.52 (d, 1H), 7.98 (d, 1H), 7.84 (s, 1H), 7.71-7.77 (m, 2H), 7.61 (d,1H), 6.24 (s, 1H), 5.75 (s, 2H), 4.37 (s, 2H), 4.29 (d, 2H), 2.14 (s,3H).

Example 30: Preparation ofN-((6-amino-2-(trifluoromethyl)pyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2-(trifluoromethyl)pyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(45 mg, 35%) was prepared as described forN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(Example 26) as a white solid. LRMS (M+H⁺) m/z calculated 472.1, found471.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.13 (t, 1H), 8.83 (d, 1H), 8.65 (d, 1H),8.53 (d, 1H), 7.98 (d, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.74 (d, 1H),7.64 (d, 1H), 7.52 (d, 1H), 6.65 (d, 1H), 6.44 (s, 2H), 4.44 (d, 2H),4.37 (s, 2H).

Example 31: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(65 mg, 45%) was prepared as described forN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(Example 26) as a white solid. LRMS (M+H⁺) m/z calculated 454.1, found453.9.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.40 (t, 1H), 8.83 (d, 1H), 8.67 (d, 1H),8.54 (s, 1H), 8.13 (d, 1H), 7.97 (d, 1H), 7.87 (s, 1H), 7.81 (s, 1H),7.74-7.76 (m, 2H), 7.69 (d, 1H), 7.55 (s, 1H), 7.40 (d, 1H), 6.84 (d,1H), 6.74 (s, 2H), 4.61 (d, 2H), 4.38 (s, 2H).

Example 32: Preparation of2-(3-chloro-quinolin-6-ylmethyl)-N-(6-fluoro-1H-indazol-5-ylmethyl)-isonicotinamide

Step 1: Preparation of 4-amino-2-fluoro-5-methyl-benzonitrile

To a solution of 4-bromo-5-fluoro-2-methyl-phenylamine (20 g, 98.0 mmol,1.0 eq) in DMF (100 mL) was added Zn(CN)2 (28.7 g, 245 mmol, 2.5 eq),followed by addition of Pd(PPh₃)₄ under N₂. The mixture was stirred at90° C. for overnight. The mixture was concentrated in vacuo and theresidue was dissolved in water, extracted with EtOAc. The combinedextracts were dried and concentrated. The residue was purified by columnchromatography on a silica gel column (PE/EtOAc=10/1, v/v) to afford4-amino-2-fluoro-5-methyl-benzonitrile as a yellow solid (13.68 g, 92%).

Step 2: Preparation of 6-fluoro-1H-indazole-5-carbonitrile

To a solution of 4-amino-2-fluoro-5-methyl-benzonitrile (13.68 g, 90.59mmol, 1.0 eq) in AcOH (450 mL) was added NaNO₂ (7.5 g, 108.7 mmol, 1.2eq). The mixture was stirred at rt for overnight. Upon completion,aqueous NaOH (50%) was added to the reaction mixture until pH 7-8. Themixture was extracted with EtOAc. The organic layer was concentratedunder pressure. The residue was purified by column chromatography on asilica gel column (PE/EtOAc=15/1, v/v) to afford6-fluoro-1H-indazole-5-carbonitrile as a white solid (5 g, 34%).

Step 3: Preparation of6-fluoro-1-(tetrahydro-pyran-2-yl)-1H-indazole-5-carbonitrile

To a solution of 6-fluoro-1H-indazole-5-carbonitrile (5 g, 31.05 mmol,1.0 eq) and 3,4-dihydro-2H-pyran (5.25 g, 62.1 mmol, 2 eq) in DCM (50mL) was added PTSA (590 mg, 3.11 mmol, 0.1 eq) and the mixture wasstirred at rt overnight. Solvent was removed in vacuo. The residue wasdissolved in EtOAc, washed with water, brine and dried over Na₂SO₄. Thecombined extracts were dried and concentrated. The residue was purifiedby chromatography on a silica gel column (PE/EtOAc=15/1, v/v) to afford6-fluoro-1-(tetrahydro-pyran-2-yl)-1H-indazole-5-carbonitrile as a brownsolid (4.39 g, 57%).

Step 4: Preparation of(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)methanamine

To a solution of6-fluoro-1-(tetrahydro-pyran-2-yl)-1H-indazole-5-carbonitrile (4.39 g,17.92 mmol, 1.0 eq) in MeOH (20 mL) was added Raney Ni (800 mg) underH₂. The mixture was stirred at rt overnight. The reaction mixture wasfiltered and the filtrate was purified by chromatography on a silica gelcolumn (PE/EtOAc=15/1, v/v) to give(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)methanamine (3.8g, 85%) as a white solid.

Step 5: Preparation of (6-fluoro-1H-indazol-5-yl)methanaminehydrochloride

To a solution of(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)methanamine (3.43g, 15.26 mmol, 1 eq) in EtOAc was added EtOAc/HCl (10M). The mixture wasstirred at rt for 3 h. The reaction mixture was filtered and thefiltrate was concentrated to give (6-fluoro-1H-indazol-5-yl)methanaminehydrochloride (3.43 mg, crude).

Step 6: Preparation of2-(3-Chloro-quinolin-6-ylmethyl)-N-(6-fluoro-1H-indazol-5-ylmethyl)-isonicotinamide

To a solution of (6-fluoro-1H-indazol-5-yl)-methylamine hydrochloride(80 mg, 0.4 mmol, 1.5 eq) in DMF (10 mL) was added2-(3-chloro-quinolin-6-ylmethyl)-isonicotinic acid (80 mg, 0.26 mmol, 1eq), HATU (122 mg, 0.32 mmol/1.2 eq), and TEA (1 mL). The reactionmixture was stirred at rt for 3 h. Then it was quenched with water,extracted with DCM. The combined extracts were dried and concentrated,and the residue was purified by prep-HPLC to give2-(3-Chloro-quinolin-6-ylmethyl)-N-(6-fluoro-1H-indazol-5-ylmethyl)-isonicotinamide(30 mg, 27%) as a white solid. LCMS (M+H⁺) m/z calculated 446.1, found446.0.

¹H NMR (DMSO-d6, 400 MHz) δ 13.09 (s, 1H), 9.26-9.28 (t, 1H), 8.83-8.84(d, 1H), 8.65-8.66 (d, 1H), 8.52-8.53 (d, 1H), 8.06 (s, 1H), 7.97-7.99(d, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.68-7.76 (m, 2H), 7.67-7.68 (d,1H), 7.32-7.35 (d, 1H), 4.56-4.57 (d, 2H), 4.38 (s, 2H), 2.50 (s, 3H).

Example 33: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(50 mg, 33%) was prepared as described forN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(Example 26) as a yellow solid. LRMS (M+H⁺) m/z calculated 479.1, found478.9.

¹H NMR (DMSO-d₆, 400 MHz): δ 11.42 (br, 1H), 9.25 (t, 1H), 8.83 (s, 1H),8.65 (d, 1H), 8.53 (s, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.79 (s, 1H),7.74 (d, 1H), 7.66 (d, 1H), 7.51 (s, 1H), 7.44 (d, 1H), 7.22 (d, 1H),4.58 (d, 2H), 4.37 (s, 2H).

Example 34: Preparation ofN-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(60 mg, 45%) was prepared as described forN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(Example 26) as a yellow solid. LRMS (M+H⁺) m/z calculated 418.1. found417.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.00 (t, 1H), 8.83 (d, 1H), 8.63 (d, 1H),8.53 (d, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.73-7.76 (m, 2H), 7.62 (d,1H), 7.77 (d, 1H), 6.26 (d, 1H), 5.85 (s, 2H), 4.36 (s, 2H), 4.28 (d,2H), 2.28 (s, 3H).

Example 35: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(40 mg, 29%) was prepared as described forN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(Example 26) as a yellow solid. LRMS (M+H⁺) m/z calculated 432.2. found432.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.83 (d, 1H), 8.64 (t, 1H), 8.60 (d, 1H),8.53 (s, 1H), 7.97 (d, 1H), 7.84 (s, 2H), 7.72-7.75 (m, 2H), 7.60 (d,1H), 6.11 (s, 1H), 5.67 (s, 2H), 4.33-4.35 (m, 4H), 2.29 (s, 3H), 2.15(s, 3H).

Example 36: Preparation ofN-((3-aminobenzo[d]isoxazol-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

N-((3-aminobenzo[d]isoxazol-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(65 mg, 46%) was prepared as described forN-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(Example 26) as a yellow solid. LRMS (M+H⁺) m/z calculated 444.1. found443.9.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.38 (t, 1H), 8.83 (d, 1H), 8.67 (s, 1H),8.53 (d, 1H), 7.99 (d, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.76 (d, 2H),7.67 (d, 1H), 7.36 (s, 1H), 7.21 (d, 1H), 6.38 (s, 2H), 4.60 (d, 2H),4.38 (s, 2H).

Example 37: Preparation ofN-(5-chloro-1H-indazol-3-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide

To a solution of methyl 2-((3-chloroquinolin-6-yl)methyl)isonicotinate(1.9 g, 6.1 mmol, 1.0 eq) in THF (15 mL)/H₂O (15 mL) was added NaOH (360mg, 9.11 mmol, 1.5 eq). The mixture was stirred at 40° C. for 1 h andwas acidified to pH 5 with 1N HCl solution to get 0.8 g of product. To asolution of the above crude product (100 mg, 0.33 mmol, 1.0 eq) and(5-chloro-1H-indazol-3-yl)-methylamine (120 mg, 0.66 mmol, 2.0 eq) inDMF (8 mL) was added HATU (152 mg, 0.4 mmol, 1.2 eq) and Et₃N (0.15 mL,0.99 mmol, 3 eq). The mixture was stirred at rt for overnight,concentrated and purified was purified by flash chromatography on asilica gel column (DCM/MeOH=10/1, v/v) to giveN-(5-chloro-1H-indazol-3-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide(46 mg, 30% for 2 steps) as a white solid. LRMS (M+H⁺) m/z calculated462.1, found 461.9.

¹H NMR (DMSO-d₆, 400 MHz) δ 13.09 (s, 1H), 9.40 (m, 1H), 8.82-8.83 (d,1H), 8.63-8.64 (d, 1H), 8.51-8.52 (d, 1H), 7.96-7.98 (d, 1H), 7.89 (s,1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.74 (d, 1H), 7.64 (d, 1H), 7.52-7.54(d, 1H), 7.32-7.34 (dd, 1H), 4.77-4.78 (d, 2H), 4.36 (s, 2H).

Example 38: Preparation ofN-(3-Chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide

To a solution of 2-(3-chloro-quinolin-6-ylmethyl)-isonicotinic acid (100mg, 0.33 mmol, 1.0 eq) and(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-methylamine (120 mg, 0.66 mmol,2.0 eq) in DMF (8 mL) was added HATU (152 mg, 0.4 mmol, 1.2 eq) and Et₃N(0.15 mL, 0.99 mmol, 3 eq). The mixture was stirred at rt for overnight,concentrated and purified was purified by flash chromatography on asilica gel column (DCM/MeOH=10/1, v/v) to giveN-(5-chloro-1H-indazol-3-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide(13 mg, 8.5%) as a white solid. LRMS (M+H⁺) m/z calculated 462.1, found461.9.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.96 (s, 1H), 9.33 (m, 1H), 8.82 (d, 1H),8.65 (d, 1H), 8.51-8.52 (d, 1H), 8.30 (d, 1H), 7.98 (d, 1H), 7.86 (m,2H), 7.63-7.77 (m, 4H), 4.57-4.59 (d, 2H), 4.36 (s, 2H).

Example 39: Preparation ofN-(6-Amino-2-methyl-pyridin-3-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide

N-(6-amino-2-methyl-pyridin-3-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide(41 mg, 30%) was prepared as described forN-(5-chloro-1H-indazol-3-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide(Example 37) as a white solid. LRMS (M+H⁺) m/z calculated 418.1, found418.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.99 (m, 1H), 8.83 (d, 1H), 8.62-8.63 (d,1H), 8.53 (d, 1H), 7.96-7.99 (d, 1H), 7.85 (s, 1H), 7.72-7.76 (m, 2H),7.61-7.63 (d, 1H), 6.21-6.23 (d, 2H), 5.75 (s, 2H), 4.36 (s, 2H), 4.27(d, 2H), 2.27 (s, 2H).

Example 40: Preparation ofN-(3-Chloro-4-fluoro-1H-indol-5-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide

N-(3-chloro-4-fluoro-1H-indol-5-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide(41 mg, 26%) was prepared as described forN-(5-chloro-1H-indazol-3-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide(Example 37) as a white solid. LRMS (M+H⁺) m/z calculated 479.1, found479.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.59 (s, 1H), 9.23 (m, 1H), 8.82 (d, 1H),8.63 (d, 1H), 8.52 (d, 1H), 7.98 (d, 1H), 7.84 (s, 1H), 7.78 (s, 1H),7.72-7.74 (d, 1H), 7.63-7.64 (d, 1H), 7.50-7.51 (d, 1H), 7.12-7.19 (m,2H), 4.55-4.57 (d, 2H), 4.36 (s, 2H).

Example 41: Preparation of2-(3-chloro-quinolin-6-ylmethyl)-N-(6-fluoro-1H-indol-5-ylmethyl)-isonicotinamide

2-(3-Chloro-quinolin-6-ylmethyl)-N-(6-fluoro-1H-indol-5-ylmethyl)-isonicotinamide(71 mg, 48%) was prepared as described forN-(5-chloro-1H-indazol-3-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide(Example 37) as a white solid. LRMS (M+H⁺) m/z calculated 445.1, found445.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.11 (s, 1H), 9.21 (m, 1H), 8.82 (d, 1H),8.63 (d, 1H), 8.53 (d, 1H), 7.96 (d, 1H), 7.66-7.85 (m, 4H), 7.47 (d,1H), 7.17-7.31 (m, 1H), 7.13 (d, 1H), 6.38 (d, 2H), 4.56 (d, 2H), 4.36(s, 2H).

Example 42: Preparation of2-((3-chloroquinolin-6-yl)methyl)-N-((2-methyl-6-(methylamino)pyridin-3-yl)methyl)isonicotinamide

To a solution of sodium methoxide (33 mg, 0.6 mmol, 5.0 eq) in MeOH (20mL), were added paraformaldehyde (36 mg, 1.2 mmol, 10.0 eq) andN-(6-amino-2-methyl-pyridin-3-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide(50 mg, 0.12 mmol, 1.0 eq). The mixture was stirred at rt for 24 h untilTLC indicated the starting material was consumed. Then sodiumborohydride (14 mg, 0.36 mmol, 3.0 eq) was added, and the mixture wasstirred at 40° C. for additional 3 h. The resulting mixture wasconcentrated and dissolved in EtOAc. The organic phase was washed withwater and brine, dried and concentrated in vacuum. The residue waspurified by prep-HPLC to give2-((3-chloroquinolin-6-yl)methyl)-N-((2-methyl-6-(methylamino)pyridin-3-yl)methyl)isonicotinamide(13 mg, 25%). LRMS (M+H⁺) m/z calculated 432.2, found 431.8.

¹H NMR (DMSO-d6, 400 MHz) δ 8.98 (t, 1H), 8.82 (d, 1H), 8.63 (d, 1H),8.52 (d, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.74 (d, 1H), 7.72 (d, 1H),7.62 (d, 1H), 7.26 (d, 1H), 6.23 (d, 1H), 6.19 (d, 1H), 4.36 (s, 2H),4.29 (d, 2H), 2.72 (d, 3H), 2.31 (s, 3H).

Example 43: Preparation ofN-((6-amino-2-cyclopropylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of 6-amino-2-chloro-nicotinonitrile

To a solution of 6-chloro-5-iodo-pyridin-2-ylamine (25.0 g, 98 mmol, 1.0eq) in DMF (200 mL) was added Zn(CN)₂ (5.7 g, 49 mmol, 0.5 eq) andPd(PPh₃)₄ (5.66 g, 4.9 mmol, 0.05 eq). The mixture was stirred at 65° C.overnight under N₂. Then EtOAc and water was added. The organic layerwas concentrated, and purified by silica gel chromatography (EA/PE=1/1,v/v) to afford 6-amino-2-chloro-nicotinonitrile (12.2 g, 81%) as ayellow solid.

Step 2: Preparation of 6-amino-2-cyclopropyl-nicotinonitrile

To a mixture of 6-amino-2-chloro-nicotinonitrile (3.0 g, 19.6 mmol, 1eq), cyclopropylboronic acid (2.2 g, 25.5 mmol, 1.3 eq), K₃PO₄ (12.4 g,58.8 mmol, 3 eq), tricyclohexylphosphine (550 mg, 1.96 mmol, 0.1 eq) in200 mL of toluene and 10 mL of water was added Pd(OAc)₂ (220 mg, 0.98mmol, 0.05 eq). The reaction mixture was stirred under reflux for 48 h.After cooling to rt, the solvent was removed by evaporation. The residuewas diluted with water and extracted with EtOAc. The combined organiclayers were dried and concentrated. The residue was purified bychromatography on silica gel column (EtOAc/PE=1/1, v/v) to give6-amino-2-cyclopropyl-nicotinonitrile (1.6 g, 51%) as a yellow solid.

Step 3: Preparation of 5-(aminomethyl)-6-cyclopropylpyridin-2-aminehydrochloride

To a solution of 6-amino-2-cyclopropyl-nicotinonitrile (700 mg, 4.4mmol, 1 eq) was added in MeOH (10 mL) and EtOH (10 mL), followed byaddition of conc. HCl. Then Pd/C was added under N₂ and the stirring wascontinued at 40° C. overnight. After filtration and washed with MeOH,the organic phase was concentrated under reduce pressure to give thecrude product (500 mg, 69%), which was used directly in the nextreaction without further purification.

Step 4: Preparation of tert-butyl(6-amino-2-cyclopropylpyridin-3-yl)methylcarbamate

To a solution of 5-ainomethyl-6-cyclopropyl-pyridin-2-ylamine (500 mg,3.06 mmol, 1 eq) and Boc₂O (920 mg, 3.68 mmol, 1.2 eq) in DCM was addedTEA (1 mL) kept stirring at rt for 2 h. Then it was washed with waterand extracted with EtOAc. After concentration under reduce pressure, theresidue was purified by chromatography on silica gel column(EtOAc/PE=1/2, v/v) to give the target compound (300 mg, 37%).

Step 5: Preparation of 5-(aminomethyl)-6-cyclopropylpyridin-2-aminehydrochloride

To a solution of tert-butyl(6-amino-2-cyclopropylpyridin-3-yl)methylcarbamate in EtOAc was addedEtOAc/HCl with stirring at rt for 2 h. After filtration and washing withEtOAc, the product (120 mg, 53%) was obtained as white solid, which wasused without purification.

Step 6: Preparation ofN-((6-amino-2-cyclopropylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

To a solution of 5-aminomethyl-6-cyclopropyl-pyridin-2-ylamine (46 mg,0.2 mmol, 1.5 eq) in DMF (10 mL) was added2-(3-chloro-quinolin-6-ylmethyl)-isonicotinic acid (40 mg, 0.13 mmol, 1eq), HOBT (22 mg, 0.16 mmol, 1.2 eq), and EDCI (30 mg, 0.16 mmol, 1.2eq). The reaction mixture was stirred at rt overnight. Then it wasquenched with water, extracted with DCM. The combined extracts weredried and concentrated, and the residue was purified by prep-HPLC togiveN-((6-amino-2-cyclopropylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide(7.7 mg, 13%) as a white solid. LRMS (M+H⁺) m/z calculated 444.2, found444.1.

¹H NMR (DMSO-d6, 400 MHz) δ 9.00 (t, 1H), 8.82 (d, 1H), 8.62 (d, 1H),8.51 (d, 1H), 7.97 (d, 2H), 7.85 (s, 1H), 7.72 (d, 2H), 7.61 (d, 2H),7.19 (d, 1H), 6.15 (d, 2H), 5.61 (s, 2H), 4.42 (d, 2H), 4.36 (s, 2H),0.83 (s, 2H), 0.71-0.74 (m, 2H).

Example 44: Preparation of2-((3-chloroquinolin-6-yl)methyl)-N-((6-(dimethylamino)-2-methylpyridin-3-yl)methyl)isonicotinamide

Step 1: Preparation of 6-(dimethylamino)-2-methylnicotinonitrile

To a solution of 6-amino-2-methyl-nicotinonitrile (2 g, 15 mmol, 1.0 eq)and CH₃I (21 mg, 150 mmol, 10 eq) in THF (10 mL) was added NaH (1.8 mg,75 mmol, 5.0 eq) under N₂. The mixture was stirred at rt overnight. Themixture was quenched with water, extracted with DCM. The combinedextracts were dried and concentrated in vacuum to provide the compound(2.2 g, 91%), which was not further purified for next step.

Step 2: Preparation of 5-(aminomethyl)-N,N,6-trimethylpyridin-2-amine

To a solution of 6-dimethylamino-2-methyl-nicotinonitrile (200 mg, 1.19mmol, 1.0 eq) in MeOH (10 mL) was added Raney Ni (400 mg) under H₂. Themixture was stirred at rt overnight. The reaction mixture was filteredand the filtrate was concentrated to provide the product (180 mg, 91%),which was directly used in next step without further purification.

Step 3: Preparation of2-((3-chloroquinolin-6-yl)methyl)-N-((6-(dimethylamino)-2-methylpyridin-3-yl)methyl)isonicotinamide

To a solution of 2-(3-chloro-quinolin-6-ylmethyl)-isonicotinic acid (326mg, 1.09 mmol, 1 eq) in DMF (10 mL) was added(5-aminomethyl-6-methyl-pyridin-2-yl)-dimethylamine (180 mg, 1.09 mmol,1 eq), HATU (497 mg, 1.3 mmol, 1.2 eq), and Et₃N (1 mL). The reactionmixture was stirred at rt for 3 h. Then it was quenched with water,extracted with DCM. The combined extracts were dried and concentrated.The residue was purified by prep-HPLC to give2-((3-chloroquinolin-6-yl)methyl)-N-((6-(dimethylamino)-2-methylpyridin-3-yl)methyl)isonicotinamide(130 mg, 30%) as a gray solid. LRMS (M+H⁺) m/z calculated 446.2, found445.8.

¹H NMR (DMSO, 400 MHz) δ 9.00-9.02 (m, 1H), 8.82 (d, 1H), 8.62 (d, 1H),8.51 (d, 1H), 7.96-7.98 (m, 1H), 7.84 (s, 1H), 7.72-7.75 (m, 2H),7.61-7.62 (m, 1H), 7.34-7.37 (m, 1H), 6.40-6.41 (m, 1H), 4.31 (d, 4H),2.96 (s, 6H), 2.35 (s, 3H).

Example 45: Preparation of2-((2-(aminomethyl)quinolin-6-yl)methyl)-N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)isonicotinamide

2-((2-(Aminomethyl)quinolin-6-yl)methyl)-N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)isonicotinamide(60 mg, 79%) was prepared as described for Example 146. LRMS (M+H⁺) m/zcalculated 474.1, found 474.1. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.53 (s,1H), 9.58 (s, 1H), 8.83 (d, 1H), 8.60 (br, 1H), 8.43 (d, 1H), 8.10 (d,1H), 8.02-8.00 (m, 3H), 7.85 (d, 1H), 7.62 (d, 1H), 7.51 (s, 1H), 7.47(d, 1H), 7.44 (d, 1H), 7.31 (s, 1H), 7.24 (d, 1H), 7.20 (d, 1H), 4.60(d, 2H), 4.57 (s, 2H), 4.40 (q, 2H).

Example 46: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2-(aminomethyl)quinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2-(aminomethyl)quinolin-6-yl)methyl)isonicotinamide(35 mg, 53%) was prepared as described for Example 146. LRMS (M+H⁺) m/zcalculated 427.2, found 427.2. ¹H NMR (CD₃OD, 400 MHz) δ 8.99 (d, 1H),8.69 (d, 1H), 8.39 (s, 1H), 8.35 (d, 1H), 8.25 (d, 1H), 8.16 (s, 1H),7.98 (d, 1H), 7.80 (d, 1H), 6.74 (s, 1H), 4.82 (s, 2H), 4.63 (s, 2H),4.59 (s, 2H), 2.63 (s, 3H), 2.50 (s, 3H).

Example 47: Preparation ofN-((3-aminobenzo[d]isoxazol-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of 5-(aminomethyl)benzo[d]isoxazol-3-aminedi(tert-butyl carbamate)

To a mixture of N-hydroxy-acetamide (964 mg, 12.86 mmol, 1.5 eq) in DMF(40 mL) was added t-BuOK (1.4 g, 12.86 mmol, 1.5 eq). After stirring for30 min at rt, 4-(aminomethyl)-2-fluorobenzonitrile di(tert-butylcarbamate) (3 g, 8.57 mmol, 1.0 eq) was added. The reaction mixture wasstirred for 5 h at rt and then concentrated. The residue was purified bycolumn chromatography on a silica gel (PE/EtOAc=4/1 to 3/1, v/v) to give5-(aminomethyl)benzo[d]isoxazol-3-amine di(tert-butyl carbamate) (2 g,64%) as a white solid. LRMS (M+H⁺) m/z calculated 364. found 364.

Step 2: Preparation of 5-aminomethyl-benzo[d]isoxazol-3-ylaminedihydrochloride

To a mixture of 5-(aminomethyl)benzo[d]isoxazol-3-amine di(tert-butylcarbamate) (2 g, 5.51 mmol, 1.0 eq) in MeOH (20 mL) was added 3N of HClin EtOAc (5 mL). After stirring for 2 h at rt, the reaction mixture wasfiltered and the filter cake was washed with Et₂O to give the crude5-aminomethyl-benzo[d]isoxazol-3-ylamine dihydrochloride (1.5 g) as awhite solid. LRMS (M+H⁺) m/z calculated 164. found 164.

Step 3: Preparation ofN-((3-aminobenzo[d]isoxazol-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide

To a solution of 2-(3-methyl-quinolin-6-ylmethyl)-isonicotinic acid (150mg, crude) in DMF (15 mL) was added5-aminomethyl-benzo[d]isoxazol-3-ylamine dihydrochloride (80 mg, 0.34mmol, 1.0 eq) followed by EDCI (98 mg, 0.51 mmol, 1.5 eq), HOBT (69 mg,0.51 mmol, 1.5 eq) and TEA (103 mg, 1.02 mmol, 3.0 eq). The reactionmixture was heated to 45° C. kept stirring for overnight. Water wasadded, and the mixture was extracted with DCM. The organic layer waswashed with water, dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by prep-HPLC to giveN-((3-aminobenzo[d]isoxazol-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(30 mg, 21%) as a yellow solid. LRMS (M+H⁺) m/z calculated 424.2, found424.0.

¹H NMR (DMSO-d₆, 400 MHz): δ 9.37 (t, 1H), 8.71 (s, 1H), 8.66 (d, 1H),8.06 (s, 1H), 7.89 (d, 1H), 7.74-7.78 (m, 3H), 7.66 (d, 1H), 7.61 (d,1H), 7.35 (s, 1H), 7.21 (d, 1H), 6.37 (s, 2H), 4.58 (d, 2H), 4.35 (s,2H), 2.46 (s, 3H).

Example 48: Preparation ofN-((3-aminobenzo[d]isoxazol-6-yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamide

N-((3-aminobenzo[d]isoxazol-6-yl) methyl)-2-((6-methylquinolin-3-yl)methyl) isonicotinamide (30 mg, 21%) was prepared as described forN-((3-aminobenzo[d]isoxazol-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(Example 47) as a yellow solid. LRMS (M+H⁺) m/z calculated 424.2, found423.9. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.40 (t, 1H), 8.81 (s, 1H), 8.66 (d,1H), 8.10 (s, 1H), 7.89 (d, 1H), 7.82 (s, 1H), 7.76 (d, 1H), 7.68 (t,2H), 7.55 (d, 1H), 7.35 (s, 1H), 7.22 (d, 1H), 6.38 (s, 2H), 4.60 (d,2H), 4.37 (s, 2H), 2.48 (s, 3H).

Example 49: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of methyl 3-chloro-8-iodoquinoline-6-carboxylate

To a solution of methyl 8-iodoquinoline-6-carboxylate (30 g, 96 mmol,1.0 eq) in AcOH (1.0 L) was added NCS (38 g, 293 mmol, 3 eq). Themixture was stirred at 100° C. overnight, The mixture was concentratedin vacuo and the residue was purified by silica gel chromatography(PE/DCM=1/1, v/v) to afford methyl3-chloro-8-iodoquinoline-6-carboxylate (15 g, 49%) as yellow solid.

Step 2: Preparation of (3-chloro-8-iodo-quinolin-6-yl)-methanol

To a solution of methyl 3-chloro-8-iodoquinoline-6-carboxylate (12 g,34.5 mmol, 1.0 eq) in dry THF (200 mL) was added lithiumtri-tert-butoxyaluminum hydride (22 g, 70 mmol, 3.4 eq) carefully. Themixture was stirred at 50° C. for 5 h under N₂ protected. Then EtOAc andwater were added. The organic layer was concentrated, and purified bysilica gel chromatography (PE/DCM=1/1, v/v) to afford(3-chloro-8-iodo-quinolin-6-yl)-methanol (7.6 g, 69%) as white solid.

Step 3: Preparation of 3-chloro-6-hydroxymethyl-quinoline-8-carbonitrile

To a solution of (3-chloro-8-iodo-quinolin-6-yl)-methanol (7.6 g, 23.8mmol, 1.0 eq) in DMF (100 mL) was added Zn(CN)₂ (2.79 g, 23.8 mmol, 1.0eq) and Pd(PPh₃)₄ (2.75 g, 2.38 mmol, 0.1 eq) carefully. The mixture wasstirred at 50° C. overnight under N₂ protected. Then EtOAc and water wasadded. The organic layer was concentrated, and purified by silica gelchromatography (PE/DCM=1/2, v/v) to afford3-chloro-6-hydroxymethyl-quinoline-8-carbonitrile (5.0 g, 96%) as yellowsolid.

Step 4: Preparation of 3-chloro-6-chloromethyl-quinoline-8-carbonitrile

A mixture of 3-chloro-6-hydroxymethyl-quinoline-8-carbonitrile (2.9 g,13.3 mmol, 1.0 eq) in SOCl₂ (50 mL) was stirred at rt for 1 h andconcentrated. The residue was dissolved in DCM and treated withsat.NaHCO₃ solution to give3-chloro-6-chloromethyl-quinoline-8-carbonitrile (2.2 g, 70%) as ayellow solid.

Step 5: Preparation of methyl2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinate

To a solution of 3-chloro-6-chloromethyl-quinoline-8-carbonitrile (2.0g, 8.47 mmol, 1.0 eq) in dioxane (40 mL) was added methyl2-(trimethylstannyl)isonicotinate (2.8 g, 9.32 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (597 mg, 0.85 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, concentrated and purified bysilica gel chromatography (DCM/MeOH=100/1, v/v) to afford methyl2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinate (1.4 g, 49%) as ayellow solid.

Step 6: Preparation of2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-isonicotinic acid

To a solution of methyl2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinate (1.4 g, 4.2 mmol,1.0 eq) in THF (5 mL) and H₂O (5 mL) was added NaOH (200 mg, 5 mmol, 1.2eq). The mixture was stirred at rt for 2 h. Then it was acidified by 1NHCl to PH=6 and extracted by EtOAc. The organic layer was concentratedto afford 2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-isonicotinic acid(1.1 g, 37%) as a white solid.

Step 7: Preparation of N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl) isonicotinamide

To a solution of 2-(3-chloro-quinolin-6-ylmethyl)-isonicotinic acid (120mg, 0.37 mmol, 1.0 eq) and (3-chloro-6-fluoro-1H-indol-5-yl)-methylaminehydrochloride (200 mg, 0.73 mmol, 2.0 eq) in DMF (10 mL) was added HATU(170 mg, 4.4 mmol, 1.2 eq) and Et₃N (1.0 mL, 7.1 mmol, 19 eq). Themixture was stirred at rt overnight, Then EtOAc and water was added. Theorganic layer was concentrated and the residue was purified by pre-HPLCto give N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl) isonicotinamide (170mg, 91%) as a yellow solid. LRMS (M+H⁺) m/z calculated 504.1, found503.8.

1H NMR (DMSO-d6, 400 MHz) δ 11.39 (s, 1H), 9.24 (m, 1H), 9.03-9.04 (d,1H), 8.71-8.72 (d, 1H), 8.64-8.66 (d, 1H), 8.40 (d, 1H), 8.19 (d, 1H),7.84 (s, 1H), 7.66-7.68 (d, 1H), 7.44-7.51 (m, 2H), 7.21-7.24 (d, 1H),4.59-4.60 (d, 2H), 4.43 (s, 2H).

Example 50: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide(130 mg, 77%) was prepared as described forN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl) isonicotinamide(Example 49) as white solid. LRMS (M+H⁺) m/z calculated 456.2, found456.8. 1H NMR (DMSO-d6, 400 MHz) δ 9.03-9.04 (d, 1H), 8.72-8.73 (d, 1H),8.59-8.66 (m, 3H), 8.38-8.39 (d, 1H), 8.18-8.19 (d, 1H), 7.79 (s, 1H),7.60-7.62 (dd, 1H), 6.15 (s, 1H), 5.77 (s, 1H), 4.41 (s, 2H), 4.34-4.35(d, 2H), 2.31 (s, 3H), 2.18 (s, 3H).

Example 51: Preparation ofN-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide(80 mg, 43%) was prepared as described forN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl) isonicotinamide(Example 49) as white solid. LRMS (M+H⁺) m/z calculated 504.1, found503.8.

¹H NMR (DMSO-d6, 400 MHz) δ 11.58 (s, 1H), 9.22 (m, 1H), 9.03-9.04 (d,1H), 8.71-8.72 (d, 1H), 8.63-8.65 (d, 1H), 8.39-8.40 (d, 1H), 8.19 (s,1H), 7.83 (s, 1H), 7.65-7.66 (m, 1H), 7.50-7.51 (d, 2H), 7.14-7.21 (m,2H). 4.57-4.59 (d, 2H), 4.42 (s, 1H)

Example 52: Preparation of2-((3-chloro-8-cyanoquinolin-6-yl)methyl)-N-((6-fluoro-1H-indol-5-yl)methyl)isonicotinamide

N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide(80 mg, 46%) was prepared as described forN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl) isonicotinamide(Example 49) as white solid. LRMS (M+H⁺) m/z calculated 469.7, found469.7.

¹H NMR (DMSO-d6, 400 MHz) δ 11.09 (s, 1H), 9.19 (m, 1H), 9.03-9.04 (d,1H), 8.72-8.73 (d, 1H), 8.64-8.65 (d, 1H), 8.39-8.40 (d, 1H), 8.19 (s,1H), 7.84 (s, 1H), 7.67-7.69 (m, 1H), 7.49-7.50 (d, 2H), 7.31-7.32 (t,1H) 7.14-7.18 (m, 2H), 6.39 (s, 1H), 4.56-4.58 (d, 2H), 4.42 (s, 1H).

Example 53: Preparation ofN-((6-amino-4-methylpyridin-3-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide(120 mg, 73%) was prepared as described forN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide (Example 49) as yellow solid. LRMS (M+H+) m/z calculated443.1, found 443.0.

¹H NMR (DMSO-d6, 400 MHz) δ 9.03-9.04 (d, 1H), 8.92-8.93 (t, 1H),8.72-8.73 (d, 1H), 8.61-8.63 (m, 3H), 8.39-8.40 (d, 1H), 8.18-8.19 (d,1H), 7.79 (s, 2H), 7.61-7.63 (dd, 1H), 6.27 (s, 1H), 5.77 (s, 1H), 4.41(s, 2H), 4.29-4.32 (d, 2H), 2.15 (s, 3H).

Example 54: Preparation of2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-N-(5-chloro-1H-indazol-3-ylmethyl)-isonicotinamide

To a solution of 2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-isonicotinicacid (100 mg, 0.31 mmol, 1.0 eq) in DCM (8 mL) was added HOBT (53 mg,0.39 mmol, 1.3 eq), EDCI (86 mg, 0.45 mmol, 1.5 eq), Et₃N (0.13 mL, 0.9mmol, 3.0 eq) and (5-chloro-1H-indazol-3-yl)-methylamine (67 mg, 0.37mmol, 1.2 eq). The mixture was stirred at rt for 12 h and diluted withwater. The organic layer was separated and the aqueous layer wasextracted with DCM. The combined extracts were dried and concentrated.The residue was purified by flash chromatography on a silica gel column(DCM/MeOH=10/1, v/v) to give2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-N-(5-chloro-1H-indazol-3-ylmethyl)-isonicotinamide(50 mg, 34%) as a white solid. LRMS (M+H⁺) m/z calculated 487.1, found486.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 13.07 (s, 1H), 9.36 (m, 1H), 9.04 (d, 1H),8.70 (d, 1H), 8.63 (d, 1H), 8.38 (d, 1H), 8.18 (s, 1H), 7.89 (d, 1H),7.82 (s, 1H), 7.64 (d, 1H), 7.53 (d, 1H), 7.31-7.34 (d, 1H), 4.78 (d,2H), 4.42 (s, 2H).

Example 55: Preparation of2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-N-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-isonicotinamide

2-(3-Chloro-8-cyano-quinolin-6-ylmethyl)-N-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-isonicotinamide(90 mg, 66%) was prepared as described for2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-N-(5-chloro-1H-indazol-3-ylmethyl)-isonicotinamide(Example 54) as a white solid. LRMS (M+H⁺) m/z calculated 487.1, found486.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.95 (s, 1H), 9.34 (m, 1H), 9.04 (d, 1H),8.71 (d, 1H), 8.64 (d, 1H), 8.39 (d, 1H), 8.31 (s, 1H), 8.19 (s, 1H),7.87 (s, 1H), 7.83 (d, 1H), 7.65-7.67 (m, 2H), 4.59-4.61 (d, 2H), 4.42(s, 2H).

Example 56: Preparation ofN-(6-amino-2-methyl-pyridin-3-ylmethyl)-2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-isonicotinamide

N-(6-amino-2-methyl-pyridin-3-ylmethyl)-2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-isonicotinamide(50 mg, 38%) was prepared as described for2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-N-(5-chloro-1H-indazol-3-ylmethyl)-isonicotinamide(Example 54) as a white solid. LRMS (M+H⁺) m/z calculated 441.9, found441.9.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.04 (m, 2H), 8.72 (d, 1H), 8.64 (d, 1H),8.39 (d, 1H), 8.19 (s, 1H), 7.80 (s, 1H), 7.63 (d, 1H), 7.38 (m, 1H),6.38 (m, 1H), 6.25 (m, 1H), 4.42 (s, 2H), 4.30 (d, 2H).

Example 57: Preparation ofN-(1-amino-isoquinolin-6-ylmethyl)-2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-isonicotinamide

N-(1-amino-isoquinolin-6-ylmethyl)-2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-isonicotinamide(100 mg, 73%) was prepared as described for2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-N-(5-chloro-1H-indazol-3-ylmethyl)-isonicotinamide(Example 54) as a white solid. LRMS (M+H⁺) m/z calculated 479.1, found479.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.39 (m, 2H), 9.04 (d, 1H), 8.72 (d, 1H),8.66 (d, 1H), 8.40 (s, 1H), 8.20 (s, 1H), 8.12-8.15 (d, 1H), 7.86 (s,1H), 7.75-7.76 (d, 1H), 7.69-7.70 (d, 1H), 7.56 (s, 1H), 7.39-7.41 (d,1H), 6.84-6.85 (d, 1H), 6.72 (s, 1H), 4.62 (d, 2H), 4.44 (s, 2H).

Example 58: Preparation of6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide

To a solution ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamidehydrochloride (100 mg, 0.22 mmol, 1.0 eq) and K₂CO₃ (215 mg, 1.56 mmol,7.3 eq) in DMSO (10 mL) was added H₂O₂ (1 mL). The mixture was stirredat 50° C. for 3 h, Then EtOAc and water was added, The organic layer wasconcentrated and purified by pre-HPLC to give6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(71 mg, 48%) as a white solid. LRMS (M+H+) m/z calculated 475.2, found474.8.

¹H NMR (DMSO-d6, 400 MHz) δ 9.62 (d, 1H), 8.96-8.98 (d, 1H), 8.59-8.70(m, 3H), 8.43-8.48 (d, 1H), 8.03-8.04 (d, 1H), 7.94 (s, 1H), 7.79 (s,1H), 7.60-7.62 (dd, 1H), 6.11 (s, 1H), 5.66 (s, 1H), 4.40 (s, 2H),4.33-4.35 (d, 2H), 2.30 (s, 3H), 2.16 (s, 3H).

Example 59: Preparation of3-chloro-6-((4-(((3-chloro-6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide

3-Chloro-6-((4-(((3-chloro-6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide(30 mg, 58%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(Example 58) as a white solid. LRMS (M+H+) m/z calculated 522.1, found521.9.

¹H NMR (DMSO-d6, 400 MHz) δ 11.39 (s, 1H), 9.63 (s, 1H), 9.24-9.26 (t,1H), 8.97-8.98 (d, 1H), 8.64-8.70 (dd, 2H), 8.44-8.45 (d, 1H), 8.04-8.05(d, 1H), 7.95-7.96 (d, 1H), 7.66-7.68 (d, 1H), 7.43-7.50 (m, 1H),7.20-7.24 (d, 1H), 4.57-4.59 (d, 2H), 4.42 (s, 2H).

Example 60: Preparation of3-chloro-6-((4-(((5-chloro-1H-indazol-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide

3-Chloro-6-((4-(((5-chloro-1H-indazol-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide(20 mg, 66%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(Example 58) as a white solid. LRMS (M+H+) m/z calculated 505.1, found504.9.

¹H NMR (DMSO-d₆, 400 MHz) δ 13.09 (s, 1H), 9.63 (s, 1H), 9.40-9.41 (t,1H), 8.97-8.98 (d, 1H), 8.64-8.70 (dd, 2H), 8.43 (s, 1H), 7.84-8.02 (m,3H), 7.64-7.65 (d, 1H), 7.51-7.54 (d, 1H), 7.31-7.32 (m, 1H), 4.77-4.79(d, 2H), 4.41 (s, 2H).

Example 61: Preparation of3-chloro-6-((4-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide

3-Chloro-6-((4-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide(30 mg, 37%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(Example 58) as a white solid. LRMS (M+H+) m/z calculated 505.1, found505.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.63 (s, 1H), 9.34-9.35 (t, 1H), 8.96-8.97(d, 1H), 8.69-8.70 (d, 1H), 8.64-8.66 (d, 1H), 8.44 (s, 1H), 8.31 (s,1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.65-7.67(d, 2H), 4.58-4.60 (d, 2H), 4.42 (s, 2H).

Example 62: Preparation of6-((4-(((6-amino-2-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide

6-((4-(((6-Amino-2-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(28 mg, 44%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(Example 58) as a white solid. LRMS (M+H+) m/z calculated 461.1, found461.1.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.63 (s, 1H), 8.97-9.00 (m, 2H), 8.70-8.71(d, 1H), 8.62-8.64 (d, 1H), 8.44-8.46 (d, 1H), 8.04 (s, 1H), 7.96 (s,1H), 7.63-7.65 (dd, 1H), 7.23-7.25 (d, 1H), 6.22-6.25 (dd, 1H), 5.77 (s,1H), 4.42 (s, 2H), 4.28-4.30 (d, 2H), 2.28 (s, 3H).

Example 63: Preparation of6-((4-(((6-amino-4-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide

6-((4-(((6-Amino-4-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(70 mg, 69%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(Example 58) as a white solid. LRMS (M+H+) m/z calculated 461.1, found461.1.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.63 (s, 1H), 8.92-9.00 (m, 2H), 8.70-8.71(d, 1H), 8.62-8.64 (d, 1H), 8.43-8.45 (d, 1H), 8.05 (s, 1H), 7.96 (s,1H), 7.78-7.80 (dd, 1H), 7.61-7.63 (d, 1H), 6.26 (s, 1H), 5.81 (s, 1H),4.41 (s, 2H), 4.29-4.31 (d, 2H), 2.15 (s, 3H).

Example 64: Preparation of6-((4-(((1-aminoisoquinolin-6-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide

6-((4-(((1-Aminoisoquinolin-6-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(25 mg, 16%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(Example 58) as a white solid. LRMS (M+H+) m/z calculated 497.1, found497.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.63 (s, 1H), 9.37-9.39 (t, 1H), 8.97-8.98(m, 2H), 8.70-8.71 (d, 1H), 8.67-8.68 (d, 1H), 8.45-8.46 (d, 1H),8.13-8.15 (d, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.75-7.76(d, 1H), 7.69-7.70 (dd, 1H), 7.54-7.56 (dd, 1H), 7.42 (s, 1H), 7.39-7.40(d, 1H), 6.84-6.86 (d, 1H), 6.76 (s, 2H), 4.60-4.62 (d, 2H), 4.40 (s,2H).

Example 65: Preparation of3-chloro-6-((4-(((3-chloro-4-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide

3-Chloro-6-((4-(((3-chloro-4-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide(35 mg, 16%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(Example 58) as a white solid. LRMS (M+H+) m/z calculated 522.1, found522.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.58 (s, 1H), 9.62 (s, 1H), 9.22-9.25 (t,1H), 8.97-8.98 (d, 2H), 8.69-8.70 (d, 1H), 8.63-8.65 (d, 1H), 8.43-8.44(d, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.82 (s, 1H), 7.65-7.66 (d, 1H),7.51 (s, 1H), 7.14-7.20 (m, 2H), 4.56-4.57 (d, 2H), 4.41 (s, 2H).

Example 66: Preparation of3-chloro-6-((4-(((6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide

3-Chloro-6-((4-(((6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide(35 mg, 42%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide(Example 58) as a white solid. LRMS (M+H+) m/z calculated 488.1, found488.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.09 (s, 1H), 9.62 (s, 1H), 9.19-9.22 (t,1H), 8.97-8.98 (d, 2H), 8.69-8.70 (d, 1H), 8.64-8.66 (d, 1H), 8.44-8.45(d, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.67-7.69 (d, 1H),7.48-7.50 (s, 1H), 7.30-7.31 (t, 2H), 7.14-7.17 (1, 1H), 4.55-4.57 (d,2H), 4.42 (s, 2H).

Example 67: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of(3-chloro-8-methanesulfonyl-quinolin-6-yl)-methanol

A mixture of (3-chloro-8-iodo-quinolin-6-yl)-methanol (7.6 g, 23.8 mmol,1 eq), sodium methanesulphinate (2.92 g, 28.6 mmol, 1.2 eq), copperiodide (452 mg, 2.38 mol, 0.1 eq), L-proline sodium salt (652 mg, 4.76mol, 0.2 eq) in 110 mL of DMSO was heated to 110° C. under nitrogen for15 h. The cooled mixture was partitioned between ethyl acetate andwater. The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate twice. The combined organic layers werewashed with brine, dried over MgSO₄, and concentrated in vacuum. Theresidue was purified by silica gel column (EtOAc/PE=1/2, v/v) to give(3-chloro-8-methanesulfonyl-quinolin-6-yl)-methanol (4.1 g, 64%) as ayellow solid.

Step 2: Preparation of3-chloro-6-chloromethyl-8-methanesulfonyl-quinoline

To (3-chloro-8-methanesulfonyl-quinolin-6-yl)-methanol (4.1 g, 15.1mmol, 1.0 eq) was added SOCl₂ (50 mL) and the mixture was stirred at rtfor 1 h. The volatiles were then removed under vacuum and the residuewas dissolved in DCM. The mixture was washed with saturated aq. NaHCO₃,dried and concentrated to give3-chloro-6-chloromethyl-8-methanesulfonyl-quinoline (4.3 g, 99%) as ayellow solid.

Step 3: Preparation of methyl2-((3-chloro-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinate

To a solution of 3-chloro-6-chloromethyl-8-methanesulfonyl-quinoline(4.3 g, 14.9 mmol, 1.0 eq) in dioxane (70 mL) was added methyl2-(trimethylstannyl)isonicotinate (4.93 g, 16.4 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (1.04 g, 1.49 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, concentrated and purified bysilica gel chromatography (DCM/MeOH=50/1, v/v) to afford methyl2-((3-chloro-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinate (2.3g, 40%) as a yellow solid.

Step 4: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

To a solution of2-(3-chloro-8-methanesulfonyl-quinolin-6-ylmethyl)-isonicotinic acid (80mg, 0.21 mmol, 1 eq) in DMF (10 mL) was added5-aminomethyl-4,6-dimethyl-pyridin-2-ylamine hydrochloride (40 mg, 0.21mmol, 1.0 eq) followed by EDCI (61 mg, 0.32 mmol, 1.5 eq), HOBT (43 mg,0.32 mmol, 1.5 eq) and TEA (64 mg, 0.64 mmol, 3.0 eq). The reactionmixture was heated to 45° C. kept stirring for overnight. Water wasadded, and the mixture was extracted with DCM. The organic layer waswashed with water, dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by prep-HPLC to giveN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(40 mg, 37%) as a yellow solid. LRMS (M+H⁺) m/z calculated 510.1, found509.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.07 (d, 1H), 8.76 (d, 1H), 8.66 (t, 1H),8.62 (d, 1H), 8.36 (d, 1H), 8.23 (s, 1H), 7.83 (s, 1H), 7.62 (d, 1H),6.12 (s, 1H), 5.70 (s, 2H), 4.47 (s, 2H), 4.34 (d, 2H), 3.56 (s, 3H),2.30 (s, 3H), 2.17 (s, 3H).

Example 68: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide (40 mg, 34%) was prepared asdescribed forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(Example 67) as a white solid. LRMS (M+H⁺) m/z calculated 557.1, found557.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.41 (s, 1H), 9.27 (t, 1H), 9.07 (d, 1H),8.76 (d, 1H), 8.67 (d, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 7.88 (s, 1H),7.68 (d, 1H), 7.51 (d, 2H), 7.46 (d, 1H), 7.23 (d, 2H), 4.59 (d, 2H),4.49 (s, 2H), 3.56 (s, 3H).

Example 69: Preparation ofN-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(40 mg, 34%) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(Example 67) as a white solid. LRMS (M+H⁺) m/z calculated 496.1, found495.7.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.07 (d, 1H), 9.01 (t, 1H), 8.76 (d, 1H),8.64 (d, 1H), 8.36 (d, 1H), 8.23 (s, 1H), 7.85 (s, 1H), 7.65 (d, 1H),7.24 (d, 1H), 6.23 (d, 1H), 5.75 (s, 2H), 4.48 (s, 2H), 4.30 (d, 2H),3.56 (s, 3H), 2.28 (s, 3H).

Example 70: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide

To a solution of methyl2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinate (300 mg, 0.95mmol, 1.0 eq) in THF (16 mL)/H₂O (4 mL) was added LiOH.H₂O (79.49 mg,1.89 mmol, 2.0 eq). The mixture was stirred at 40° C. for 1 h and wasacidified to pH 5 with 1N HCl solution. The mixture was concentrated invacuo and the residue was directly used without further purification. Toa solution of the above crude product and5-aminomethyl-4,6-dimethyl-pyridin-2-ylamine (285 mg, 1.89 mmol, 2.0 eq)in DMF 10 mL) was added HOBT (192.37 mg, 1.43 mmol, 1.5 eq), EDCI(310.08 mg, 1.62 mmol, 1.7 eq) and Et₃N (0.53 mL, 3.8 mmol, 4 eq). Themixture was stirred at rt for overnight and diluted with water. Theorganic layer was separated and the aqueous layer was extracted withDCM. The combined extracts were dried and concentrated. The residue waspurified by prep-HPLC to giveN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide (90 mg, 21% for 2 steps) as an off-white solid.LRMS (M+H⁺) m/z calculated 437.2, found 437.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.89 (s, 1H), 8.61 (t, 2H), 8.23 (s, 2H),8.10 (s, 1H), 7.78 (s, 1H), 7.61 (t, 1H), 6.12 (s, 1H), 5.67 (s, 2H),4.37 (s, 2H), 4.35 (d, 2H), 2.50 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H).

Example 71: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide(105 mg, 24% for 2 steps) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide(Example 70) as an off-white solid. LRMS (M+H⁺) m/z calculated 459.2,found 459.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.41 (t, 1H), 8.90 (s, 1H), 8.69 (d, 1H),8.28 (d, 2H), 8.16 (d, 2H), 7.86 (s, 1H), 7.78 (d, 1H), 7.71 (d, 1H),7.57 (s, 1H), 7.43 (d, 1H), 6.87 (d, 1H), 6.78 (s, 2H), 4.64 (d, 2H),4.42 (s, 2H), 2.50 (s, 3H).

Example 72: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide(100 mg, 21% for 2 steps) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide(Example 70) as an off-white solid. LRMS (M+H⁺) m/z calculated 484.1,found 483.9.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.32 (s, 1H), 8.90 (t, 1H), 8.67 (d, 1H),8.62 (d, 1H), 8.27 (d, 2H), 8.12 (s, 1H), 7.83 (s, 1H), 7.68 (d, 1H),7.52 (d, 1H), 7.46 (d, 1H), 7.25 (d, 1H), 4.61 (d, 2H), 4.41 (s, 2H),2.50 (s, 3H).

Example 73: Preparation ofN-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide

To a solution of 2-(8-cyano-3-methyl-quinolin-6-ylmethyl)-isonicotinicacid (100 mg, 0.33 mmol, 1.0 eq) and(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-methylamine hydrochloride (144mg, 0.66 mmol, 2.0 eq) in DMF (5 mL) was added HATU (188 mg, 0.50 mmol,1.5 eq) and Et₃N (134 mg, 1.32 mmol, 4 eq). The mixture was stirred atrt for 2 h and diluted with water. The organic layer was separated andthe aqueous layer was extracted with DCM. The combined extracts weredried and concentrated. The residue was purified by prep-HPLC to giveN-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide(66 mg, 43%) as an off-white solid. LRMS (M+H⁺) m/z calculated 467.1,found 466.8. ¹H NMR (DMSO-d₆, 400 MHz) δ: 11.97 (s, 1H), 9.34 (t, 1H),8.89 (s, 1H), 8.66 (d, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.23 (s, 1H),8.11 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.68 (d, 1H), 7.66 (d, 1H),4.61 (d, 2H), 4.40 (s, 2H), 2.50 (s, 3H).

Example 74: Preparation ofN-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide(70 mg, 44%) was prepared as described forN-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide(Example 73) as an off-white solid. LRMS (M+H⁺) m/z calculated 484.1,found 483.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.59 (s, 1H), 9.23 (t, 1H), 8.80 (d, 1H),8.65 (d, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.81 (s, 1H), 7.65 (d, 1H),7.52 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 4.58 (d, 2H), 4.39 (s, 2H),2.50 (s, 3H).

Example 75: Preparation ofN-((5-chloro-1H-indazol-3-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide

N-((5-chloro-1H-indazol-3-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide(74 mg, 48%) was prepared as described forN-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide(Example 73) as an off-white solid. LRMS (M+H⁺) m/z calculated 467.1,found 466.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 13.09 (s, 1H), 9.38 (t, 1H), 8.90 (d, 1H),8.65 (d, 1H), 8.25 (s, 2H), 8.12 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H),7.64 (d, 1H), 7.53 (d, 1H), 7.34 (d, 1H), 7.32 (d, 1H), 4.79 (d, 2H),4.39 (s, 2H), 2.50 (s, 3H).

Example 76: Preparation of2-((8-cyano-3-methylquinolin-6-yl)methyl)-N-((6-fluoro-1H-indol-5-yl)methyl)isonicotinamide

2-((8-Cyano-3-methylquinolin-6-yl)methyl)-N-((6-fluoro-1H-indol-5-yl)methyl)isonicotinamide(70 mg, 46%) was prepared as described forN-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide(Example 73) as an off-white solid. LRMS (M+H⁺) m/z calculated 450.2,found 449.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.11 (s, 1H), 9.20 (t, 1H), 8.90 (d, 1H),8.65 (d, 1H), 8.26 (t, 2H), 8.13 (s, 1H), 7.83 (s, 1H), 7.68 (d, 1H),7.31 (d, 1H), 7.17 (d, 1H), 6.40 (s, 1H), 4.57 (d, 2H), 4.40 (s, 2H),2.50 (s, 3H).

Example 77: Preparation of6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide

To a solution ofN-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(8-cyano-3-methyl-quinolin-6-ylmethyl)-isonicotinamide(80 mg, 0.18 mmol, 1.0 eq) and K₂CO₃ (180.7 mg, 1.31 mmol, 7.3 eq) inDMSO (10 mL) was added H₂O₂ (1 mL). The mixture was stirred at 50° C.for 3 h, then EtOAc and water was added, the organic layer wasconcentrated and purified by pre-HPLC to give6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(4 mg, 4.8%) as a white solid. LRMS (M+H+) m/z calculated 455.2, found454.9.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.20 (s, 1H), 8.84 (s, 1H), 8.66 (s, 1H),8.63 (s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.90 (s, 1H),7.78 (s, 1H), 7.61 (s, 1H), 6.12 (s, 1H), 5.68 (s, 2H), 4.38 (d, 2H),4.34 (s, 2H), 2.50 (s, 3H), 2.29 (s, 3H), 2.21 (s, 3H).

Example 78: Preparation of6-((4-(((3-chloro-6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide

6-((4-(((3-chloro-6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(40 mg, 32%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(Example 77) as a off-white solid. LRMS (M+H⁺) m/z calculated 502.1,found 501.8. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.44 (s, 1H), 10.28 (d, 1H),9.31 (t, 1H), 8.89 (s, 1H), 8.71 (d, 1H), 8.48 (s, 1H), 8.28 (s, 1H),8.02 (s, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.72 (d, 1H), 7.55 (d, 1H),7.50 (d, 1H), 7.29 (d, 1H), 4.64 (d, 2H), 4.45 (s, 2H), 2.54 (s, 3H).

Example 79: Preparation of6-((4-(((1-aminoisoquinolin-6-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide

6-((4-(((1-Aminoisoquinolin-6-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(35 mg, 48%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(Example 77) as a white solid. LRMS (M+H⁺) m/z calculated 477.2, found476.9.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.22 (s, 1H), 9.40 (t, 1H), 8.85 (d, 1H),8.68 (d, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 8.15 (d, 1H), 8.00 (s, 1H),7.89 (d, 1H), 7.76 (d, 1H), 7.70 (d, 1H), 7.56 (s, 1H), 7.42 (d, 2H),6.86 (d, 1H), 6.76 (s, 2H), 4.62 (d, 2H), 4.42 (s, 2H), 2.50 (s, 3H).

Example 80: Preparation of6-((4-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide

6-((4-(((3-Chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(20 mg, 38%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(Example 77) as a white solid. LRMS (M+H⁺) m/z calculated 485.1, found484.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 10.23 (s, 1H), 9.36 (t, 1H), 8.84 (d, 1H),8.66 (d, 1H), 8.43 (d, 1H), 8.31 (d, 1H), 8.24 (s, 1H), 7.98 (d, 1H),7.88 (s, 2H), 7.80 (s, 1H), 7.67 (s, 1H), 7.66 (d, 1H), 4.60 (d, 2H),4.40 (s, 2H), 2.51 (s, 3H).

Example 81: Preparation of6-((4-(((3-chloro-4-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide

6-((4-(((3-Chloro-4-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(30 mg, 41%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(Example 77) as a white solid. LRMS (M+H+) m/z calculated 502.1, found501.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.59 (s, 1H), 10.23 (s, 1H), 9.26 (t, 1H),8.85 (d, 1H), 8.65 (d, 1H), 8.42 (d, 1H), 8.25 (s, 1H), 7.98 (d, 1H),7.88 (d, 1H), 7.80 (s, 1H), 7.66 (d, 1H), 7.51 (d, 1H), 7.21 (d, 1H),7.16 (d, 1H), 4.58 (d, 2H), 4.40 (s, 2H), 2.51 (s, 3H).

Example 82: Preparation of6-((4-(((5-chloro-1H-indazol-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide

6-((4-(((5-Chloro-1H-indazol-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(20 mg, 48%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(Example 77) as a white solid. LRMS (M+H+) m/z calculated 485.1, found484.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 13.08 (s, 1H), 10.21 (s, 1H), 9.39 (s, 1H),8.84 (s, 1H), 8.65 (d, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.97 (s, 1H),7.89 (s, 2H), 7.80 (s, 1H), 7.64 (d, 1H), 7.53 (d, 1H), 7.34 (d, 1H),4.78 (d, 2H), 4.39 (s, 2H), 2.50 (s, 3H).

Example 83: Preparation of6-((4-(((6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide

6-((4-(((6-fluoro-1H-indol-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(20 mg, 35%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide(Example 77) as a white solid. LRMS (M+H+) m/z calculated 468.2, found467.8.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.11 (s, 1H), 10.23 (s, 1H), 9.23 (t, 1H),8.84 (s, 1H), 8.66 (d, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 7.99 (s, 1H),7.90 (s, 1H), 7.83 (s, 1H), 7.69 (d, 1H), 7.51 (d, 1H), 7.18 (s, 1H),7.18 (d, 1H), 6.40 (s, 1H), 4.57 (d, 2H), 4.41 (s, 2H), 2.51 (s, 3H).

Example 84: Preparation of6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxylicacid

Step 1: Preparation of methyl6-((4-(methoxycarbonyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxylate

A mixture of methyl2-((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinate (500 mg, 1.58mmol, 1 eq) in HCl/MeOH (10M, 25 mL) was heated under reflux for oneweek. After cooling to rt, solvent was removed by evaporation. Theresidue was diluted with DCM and washed with sat.NaHCO₃. The organicphase was separated, dried and concentrated. The residue was purified bychromatography on silica gel column (EtOAc/PE=2/1, v/v) to give methyl6-44-(methoxycarbonyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxylate(100 mg, 18%) as a yellow solid.

Step 2: Preparation of6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxylicacid

To a solution of methyl6-((4-(methoxycarbonyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxylate(100 mg, 0.31 mmol, 1.0 eq) in THF/H₂O (5 mL, 1:1) was added LiOH.H₂O(39 mg, 0.93 mmol, 3 eq). The mixture was stirred at rt for 5 h and thenconcentrated. To a solution of the above crude product and5-aminomethyl-4,6-dimethyl-pyridin-2-ylamine hydrochloride (88 mg, 0.47mmol, 1.5 eq) in DMF (5 mL) was added HATU (188 mg, 0.50 mmol, 1.5 eq)and Et₃N (134 mg, 1.32 mmol, 4 eq). The mixture was stirred at rt for 2h and diluted with water. The organic layer was separated and theaqueous layer was extracted with DCM, the combined extracts were driedand concentrated. The residue was purified by prep-HPLC to give6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxylicacid (2 mg, 1.4% for 2 steps) as an off-white solid. LRMS (M+H⁺) m/zcalculated 456.2, found 455.9.

¹H NMR (CD₃OD, 400 MHz) δ 8.80 (s, 1H), 8.60 (d, 1H), 8.33 (s, 1H), 8.27(s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.31 (d, 1H), 6.32 (s, 1H), 4.49(s, 2H), 4.43 (s, 2H), 2.57 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H).

Example 85: Preparation ofN-((6-amino-4-methylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide

Step 1: Preparation of dimethoxy-acetic acid

To a solution of ethyl 2,2-dimethoxyacetate (30 g, 170 mmol, 1.0 eq) inTHF (100 mL) and H₂O (100 mL) was added NaOH (8.2 g, 205 mmol, 1.2 eq).The mixture was stirred at rt for 2 h. Then it was acidified by 1N HClto PH=6 and extracted by EtOAc. The organic layer was concentrated toafford dimethoxy-acetic acid (15 g, 59%) as a yellow oil.

Step 2: Preparation of N-(3-chloro-benzyl)-2,2-dimethoxy-acetamide

To a solution of dimethoxy-acetic acid (15 g, 100 mmol, 1.1 eq) and3-chloro-benzylamine (13 g, 92 mmol, 1.0 eq) in DMF (200 mL) was addedHATU (40 g, 100 mmol, 1.1 eq) and Et₃N (38 mL, 300 mmol, 3 eq). Themixture was stirred at rt overnight. Then EtOAc and water was added, theorganic layer was concentrated and the residue was purified bychromatography on a silica gel column (PE/EtOAc=10/1-1/1, v/v) to giveN-(3-chloro-benzyl)-2,2-dimethoxy-acetamide (13.5 g, 50%) as a yellowoil.

Step 3: Preparation of2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-isonicotinic acid

To a solution of methyl2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinate (350 mg, 1.1mmol, 1.0 eq) in THF (5 mL) and H₂O (5 mL) was added NaOH (51 mg, 1.3mmol, 1.2 eq). The mixture was stirred at rt for 2 h. Then it wasacidified by 1N HCl to PH=6 and extracted by EtOAc. The organic layerwas concentrated to afford2-(3-chloro-8-cyano-quinolin-6-ylmethyl)-isonicotinic acid (320 mg, 91%)as a white solid.

Step 4: Preparation ofN-((6-amino-4-methylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide

To a solution of2-(7-chloro-3-oxo-3H-isoquinolin-2-ylmethyl)-isonicotinic acid (50 mg,0.16 mmol, 1.0 eq) and 5-aminomethyl-4-methyl-pyridin-2-ylaminehydrochloride (57 mg, 0.33 mmol, 2.0 eq) in DMF (10 mL) was added HATU(73 mg, 0.19 mmol, 1.2 eq) and Et₃N (1.0 mL, 7.1 mmol, 44 eq). Themixture was stirred at rt for overnight, then EtOAc and water was added.The organic layer was concentrated and the residue was purified bypre-HPLC to giveN-((6-amino-4-methylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide(25 mg, 36%) as white solid. LRMS (M+H⁺) m/z calculated 434.1, found434.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.05 (s, 1H), 9.88-9.90 (t, 1H), 8.68-8.69(d, 1H), 8.88-8.93 (m, 1H), 7.77 (s, 1H), 7.67-7.72 (m, 3H), 7.41 (d,1H), 6.25 (s, 1H), 5.76 (s, 2H), 5.57 (s, 2H), 4.29-4.30 (d, 2H), 2.13(s, 3H).

Example 86: Preparation ofN-((6-amino-2-methylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide(27 mg, 37%) was prepared as described forN-((6-amino-4-methylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide(Example 85) as white solid. LRMS (M+H⁺) m/z calculated 434.1, found434.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.05-9.07 (t, 1H), 9.04 (s, 1H), 8.69-8.70(t, 1H), 8.17 (d, 1H), 7.90-7.92 (m, 1H), 7.67-7.63 (m, 2H), 7.41 (s,3H), 7.23-7.26 (d, 1H), 6.22-6.24 (d, 1H), 5.76 (s, 1H), 5.57 (s, 2H),4.28-4.30 (d, 2H), 2.27 (s, 3H).

Example 87: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide(30 mg, 42%) was prepared as described forN-((6-amino-4-methylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide(Example 85) as white solid. LRMS (M+H⁺) m/z calculated 448.1, found448.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.04 (s, 1H), 8.71-8.73 (t, 1H), 8.66-8.68(d, 1H), 8.17-8.18 (d, 1H), 7.87-7.92 (m, 2H), 7.67-7.70 (m, 2H), 7.40(s, 1H), 6.11 (s, 1H), 5.70 (s, 2H), 5.56 (s, 2H), 4.33-4.34 (d, 2H),2.29 (s, 3H), 2.15 (s, 3H).

Example 88: Preparation of2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)-N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)isonicotinamide

2-((7-Chloro-3-oxoisoquinolin-2(3H)-yl)methyl)-N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)isonicotinamide(55 mg, 70%) was prepared as described forN-((6-amino-4-methylpyridin-3-yl)methyl)-2-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide(Example 85) as white solid. LRMS (M+H⁺) m/z calculated 495.1, found495.0.

¹H NMR (DMSO-d₆, 400 MHz) δ 11.40 (s, 1H), 9.33-9.35 (t, 1H), 9.04 (s,1H), 8.72-8.73 (d, 1H), 8.17 (s, 1H), 8.89-8.94 (m, 2H), 7.69-7.70 (d,1H), 7.66-7.67 (d, 1H), 7.50-7.51 (d, 1H), 7.24-7.45 (m, 2H), 7.21-7.24(d, 1H), 5.59 (D, 2H), 4.58-4.60 (d, 2H).

Example 89: Preparation ofN-(6-amino-2-methyl-pyridin-3-ylmethyl)-2-(3-chloro-quinolin-6-ylmethyl)-isonicotinamide

Step 1: Preparation of methyl 8-fluoroquinoline-6-carboxylate

A mixture of methyl 4-amino-3-fluorobenzoate (35 g, 0.207 mmol, 1 eq),acrolein (17.4 g, 0.311 mol, 1.5 eq) and 6N HCl (600 mL) was stirred at100° C. for 10 min. Then the mixture was cooled and adjusted to pH˜5-6using NaHCO₃ (aq). The mixture was extracted with DCM. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered thenconcentrated and purified by column chromatography (EtOAc/PE=1/20, v/v)to give methyl 8-fluoroquinoline-6-carboxylate (11 g, 21%) as a yellowsolid.

Step 2: Preparation of methyl 3-chloro-8-fluoroquinoline-6-carboxylate

To a solution of methyl 8-fluoroquinoline-6-carboxylate (11 g, 53.7mmol, 1 eq) in DMF was added NCS (21.4 g, 0.161 mol, 3 eq). The reactionmixture was stirred at 120° C. overnight. The reaction mixture wasallowed to cool to ambient temperature, treated with water, neutralizedwith solid NaHCO₃ and further stirred at rt for 30 min. Finally,powdered sodium thiosulfate was carefully added to remove excess of NCS.The mixture was extracted with EtOAc. The organic layer was dried andconcentrated under vacuum. The crude product was purified byflash-chromatography on silica gel to afford methyl3-chloro-8-fluoroquinoline-6-carboxylate (11.5 g, 90%) as a yellowsolid.

Step 3: Preparation of (3-chloro-8-fluoro-quinolin-6-yl)-methanol

To a solution of methyl 3-chloro-8-fluoroquinoline-6-carboxylate (4.5 g,18.8 mmol, 1 eq) was added LiAlH(t-BuO)₃ (12.0 g, 47.1 mmol, 2.5 eq).The resulting mixture was stirred at 40° C. for 12 h and then quenchedby the addition of water. The mixture was extracted with EtOAc. Thecombined extracts were dried and concentrated. The residue was purifiedby silica gel chromatography (PE/EtOAc=2/1, v/v) to afford(3-chloro-8-fluoro-quinolin-6-yl)-methanol (2.1 g, 53%) as a yellowsolid.

Step 4: Preparation of 3-chloro-6-chloromethyl-8-fluoro-quinoline

A mixture of 3-chloro-8-fluoro-6-hydroxymethyl-quinoline (2.1 g, 9.95mmol, 1.0 eq) in SOCl₂ (50 mL) was stirred at rt for 1 h andconcentrated. The residue was dissolved in DCM and treated withsat.NaHCO₃ solution to give 3-chloro-6-chloromethyl-8-fluoro-quinoline(2.2 g, 96%) as a yellow solid.

Step 5: Preparation of methyl2-((3-chloro-8-fluoroquinolin-6-yl)methyl)isonicotinate

To a solution of 3-chloro-6-chloromethyl-8-fluoro-quinoline (2.2 g, 9.61mmol, 1.0 eq) in dioxane (60 mL) was added methyl2-(trimethylstannyl)isonicotinate (3.18 g, 10.6 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (674 mg, 0.96 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, concentrated and purified bysilica gel chromatography (DCM/MeOH=200/1, v/v) to afford methyl2-((3-chloro-8-fluoroquinolin-6-yl)methyl)isonicotinate (1.6 g, 50%) asa yellow solid.

Step 6: Preparation of2-((3-chloro-8-fluoroquinolin-6-yl)methyl)isonicotinic acid

To a solution of methyl2-((3-chloro-8-fluoroquinolin-6-yl)methyl)isonicotinate (800 mg, 2.4mmol, 1 eq) in THF (20 ml)/water (10 ml) was added NaOH (116 mg, 0.29mmol, 1.2 eq). The mixture was stirred at rt for 3 h. Then aqueous HCl(2N) was added to the reaction mixture until pH 6-7. The mixture wasextracted with EtOAc, and the organic layer was concentrated underpressure. The gray compound was directly used in next step (500 mg,76%).

Step 7: Preparation ofN-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-isonicotinamide

To a solution of 2-(3-chloro-quinolin-6-ylmethyl)-isonicotinic acid (100mg, 0.3 mmol, 1 eq) in DMF (10 mL) was added 5-aminomethyl-4,6-dimethyl-pyridin-2-ylamine (71 mg, 0.47 mmol, 1.5 eq), HATU (137 mg,0.36 mmol, 1.2 eq) and Et₃N (1 mL). The mixture was stirred at rt for 3h. Then it was quenched with water, extracted with DCM. The combinedextracts were dried, concentrated, and the residue was purified byprep-HPLC to giveN-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-isonicotinamide(39 mg, 29%) as a white solid. LRMS (M+H⁺) m/z calculated 450.1, found449.8.

¹H NMR (DMSO-d6, 400 MHz) δ: 8.88 (d, 1H), 8.60-8.62 (m, 3H), 7.75 (s,1H), 7.68 (s, 1H), 7.58-7.61 (m, 2H), 6.13 (s, 1H), 5.71 (s, 2H), 4.33(s, 4H), 2.30 (s, 3H), 2.16 (s, 3H).

Example 90: Preparation ofN-(3-chloro-6-fluoro-1H-indol-5-ylmethyl)-2-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-isonicotinamide

N-(3-chloro-6-fluoro-1H-indol-5-ylmethyl)-2-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-isonicotinamide(47 mg, 20%) was prepared as described forN-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-isonicotinamide(Example 89) as a white solid; LRMS (M+H⁺) m/z calculated 497.1, found497.7.

¹H NMR (DMSO-d6, 400 MHz) δ 11.38 (s, 1H), 9.23 (s, 1H), 8.88 (s, 1H),8.61-8.66 (m, 2H), 7.80 (s, 1H), 7.59-7.69 (m, 3H), 7.43-7.50 (m, 2H),7.20-7.23 (d, 1H), 4.57-4.59 (d, 2H), 4.36 (s, 2H).

Example 91: Preparation ofN-(6-amino-2-methyl-pyridin-3-ylmethyl)-2-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-isonicotinamide

N-(6-amino-2-methyl-pyridin-3-ylmethyl)-2-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-isonicotinamide(45 mg, 22%) was prepared as described forN-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-isonicotinamide(Example 89) as a white solid. LRMS (M+H⁺) m/z calculated 436.1, found436.0.

¹H NMR (DMSO-d6, 400 MHz) δ 8.97 (s, 1H), 8.88 (s, 1H), 8.6-8.64 (m,2H), 7.77 (s, 1H), 7.68 (s, 1H), 7.59-7.63 (m, 2H), 7.42 (d, 1H), 6.26(d, 1H), 5.80 (d, 2H), 4.35 (s, 2H), 4.29 (d, 2H).

Example 92: Preparation of methyl6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylate

To a solution of 5-aminomethyl-4,6-dimethyl-pyridin-2-ylamine (95 mg,0.43 mmol, 1.7 eq) in DMF (10 mL) was added2-((3-chloro-8-(methoxycarbonyl)quinolin-6-yl)methyl)isonicotinic acid(90 mg, 0.25 mmol, 1 eq), HATU (123 mg, 0.32 mmol, 1.3 eq), and Et₃N(0.5 mL). The mixture was stirred at rt overnight. Then it was quenchedwith water, extracted with DCM. The combined extracts were dried,concentrated, and the residue was purified by column chromatography(DCM/MeOH=20/1, v/v) to give methyl6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylate (100 mg,81.9%) as a yellow solid. LRMS (M+H⁺) m/z calculated 490.2, found 490.1.

¹H NMR (DMSO-d6, 400 MHz) δ 8.89-8.90 (m, 1H), 8.59-8.63 (m, 3H), 8.00(s, 1H), 7.91-7.92 (m, 1H), 7.77 (s, 1H), 7.60 (d, 1H), 6.15 (s, 1H),4.37 (s, 2H), 4.33-4.34 (d, 2H), 3.88 (s, 3H), 2.31 (s, 3H), 2.18 (s,3H).

Example 93: Preparation of6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylicacid

To a solution of methyl6-((4-((6-amino-2,4-dimethylpyridin-3-yl)methylcarbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylate(50 mg, 0.1 mmol, 1 eq) in THF (10 mL) was added a solution NaOH (4.9mg, 0.12 mmol, 1.2 eq) in water (2 mL) and kept stirring at rt for 3 h.Then it was acidified to pH 5 with AcOH. The mixture was concentrated invacuo and purified by a prep-HPLC to give6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylic acid (31.3 mg,65.7%) as a gray solid. LRMS (M+H⁺) m/z calculated 476.1, found 476.1.

¹H NMR (DMSO-d6, 400 MHz) δ 8.99 (s, 1H), 8.74 (s, 1H), 8.59-8.62 (m,2H), 8.18 (s, 1H), 8.04 (s, 1H), 7.79 (s, 1H), 7.60 (d, 1H), 6.11 (s,1H), 5.64 (s, 2H), 4.39 (s, 2H), 4.33 (d, 2H), 2.29 (s, 3H), 2.16 (s,3H).

Example 94: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-(hydroxymethyl)quinolin-6-yl)methyl)isonicotinamide

To a solution of methyl6-((4-((6-amino-2,4-dimethylpyridin-3-yl)methylcarbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylate(100 mg, 0.2 mmol, 1 eq) in dry THF was added drop wise LiAlH₄ below−78° C. under N₂ over a period of 20 min. The reaction mixture wasstirred for 5 h, and then it was quenched with potassium sodium tartrateand extracted with EtOAc. The combine extracts were dried, concentratedand the residue was purified by prep-HPLC to giveN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-(hydroxymethyl)quinolin-6-yl)methyl)isonicotinamide(6.5 mg, 7%) as a white solid. LRMS (M+H⁺) m/z calculated 462.2, found462.1.

¹H NMR (DMSO-d6, 400 MHz) δ 8.81 (d, 1H), 8.59-8.63 (m, 2H), 8.50 (d,1H), 7.77 (s, 1H), 7.72 (d, 2H), 7.59 (d, 1H), 6.13 (s, 1H), 5.72 (s,2H), 5.26-5.28 (t, 1H), 5.07 (d, 1H), 4.32-4.33 (m, 4H), 2.30 (s, 3H),2.16 (s, 3H).

Example 95: Preparation of methyl6-((4-(((6-amino-2-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylate

To a solution of 5-aminomethyl-6-methyl-pyridin-2-ylamine (89 mg, 0.43mmol, 1.7 eq) in DMF (10 mL) was added2-((3-chloro-8-(methoxycarbonyl)quinolin-6-yl)methyl)isonicotinic acid(90 mg, 0.25 mmol, 1 eq), HATU (123 mg, 0.32 mmol, 1.3 eq), and Et₃N(0.5 mL). The mixture was stirred at rt overnight. Then it was quenchedwith water, extracted with DCM. The combined extracts were dried andconcentrated, the residue was purified on a silica gel column(DCM/MeOH=20/1, v/v) to give methyl6-((4-(((6-amino-2-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylate(100 mg, 84.7%) as a yellow solid. LRMS (M+H⁺) m/z calculated 476.1,found 476.1.

¹H NMR (DMSO-d6, 400 MHz) δ 8.98 (t, 1H), 8.90 (m, 1H), 8.61-8.63 (m,2H), 8.00 (d, 1H), 7.92 (d, 1H), 7.79 (s, 1H), 7.62 (d, 1H), 7.25 (d,1H), 6.25 (d, 1H), 5.81 (s, 2H), 4.38 (s, 2H), 4.28 (d, 2H), 3.89 (s,3H), 2.28 (s, 3H).

Example 96: Preparation of6-((4-(((6-amino-2-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylicacid

6-((4-(((6-Amino-2-methylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylicacid (54 mg, 83.59%) was prepared as described for6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylicacid (Example 93) as a white solid. LRMS (M+H⁺) m/z calculated 462.1,found 462.1.

¹H NMR (DMSO-d6, 400 MHz) δ 9.07 (d, 1H), 8.99 (s, 1H), 8.83 (d, 1H),8.62 (d, 1H), 8.41 (m, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.62 (d, 1H),7.24 (d, 2H), 6.21 (d, 1H), 5.72 (s, 1H), 4.45 (s, 2H), 4.28 (d, 2H),2.27 (s, 3H).

Example 97: Preparation ofN-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-8-(hydroxymethyl)quinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-8-(hydroxymethyl)quinolin-6-yl)methyl)isonicotinamide(12.8 mg, 13.6%) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-(hydroxymethyl)quinolin-6-yl)methyl)isonicotinamide(Example 94) as a white solid. LRMS (M+H⁺) m/z calculated 448.1, found448.1.

¹H NMR (DMSO-d6, 400 MHz) δ 8.98 (m, 1H), 8.80 (d, 1H), 8.62 (d, 1H),8.50 (d, 1H), 7.72 (t, 3H), 7.62 (d, 1H), 7.24 (d, 1H), 6.24 (d, 1H),5.75 (s, 2H), 5.27 (m, 1H), 5.08 (d, 2H), 4.35 (s, 2H), 4.27 (d, 1H),2.27 (s, 3H).

Example 98: Preparation of6-amino-3-((2-((3-chloroquinolin-6-yl)methyl)isonicotinamido)methyl)-2,4-dimethylpyridine1-oxide

To a solution ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide (50 mg, 0.11 mmol, 1 eq) in dry DCM was added m-CPBA.The reaction mixture was stirred for 3 h. Then it was quenched withpotassium sodium tartrate and extracted with DCM. The combine extractswere dried, concentrated and the residue was purified by prep-HPLC togive6-amino-3-((2-((3-chloroquinolin-6-yl)methyl)isonicotinamido)methyl)-2,4-dimethylpyridine1-oxide (12.8 mg, 13.6%) as a white solid. LRMS (M+H⁺) m/z calculated448.1, found 448.1.

¹H NMR (DMSO-d6, 400 MHz) δ 8.82 (s, 1H), 8.73 (t, 1H), 8.60-8.61 (d,1H), 8.51 (d, 1H), 7.96 (d, 1H), 7.84 (s, 1H), 7.70-7.73 (m, 2H), 7.57(d, 1H), 6.70 (s, 2H), 6.53 (s, 1H), 4.34 (m, 4H), 2.41 (s, 3H), 2.23(s, 3H).

Example 99: Preparation of6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline1-oxide

Step 1: Preparation of 3-chloro-6-chloromethyl-quinoline 1-oxide

To a solution of 3-chloro-6-chloromethyl-quinoline (500 mg, 2.37 mmol, 1eq) in dry DCM (20 mL) was added m-CPBA (1.23 g, 7.11 mmol, 3 eq). Themixture was stirred at 40° C. for 5 h. Then the reaction was quenched bysat. NaHCO₃ and extracted with DCM. The combined organic layers weredried and concentrated. The residue was purified by chromatography on asilica gel column (EtOAc/PE=1/3, v/v) to give3-chloro-6-chloromethyl-quinoline 1-oxide (400 mg, 74%) as a yellowsolid.

Step 2: Preparation of3-chloro-6-((4-(methoxycarbonyl)pyridin-2-yl)methyl)quinoline 1-oxide

To a solution of 3-chloro-6-chloromethyl-quinoline 1-oxide (400 mg, 1.76mmol, 1.0 eq) in dioxane (10 mL) was added methyl2-(trimethylstannyl)isonicotinate (583 mg, 1.94 mmol, 1.1 eq) andPd(PPh₃)₂Cl₂ (126 mg, 0.18 mmol, 0.1 eq). The mixture was stirred at 90°C. for 3 h under nitrogen atmosphere, then concentrated and purified bysilica gel chromatography (DCM/MeOH=100/1, v/v) to afford3-chloro-6-((4-(methoxycarbonyl)pyridin-2-yl)methyl)quinoline 1-oxide(210 mg, 36%) as a yellow solid.

Step 3: Preparation of6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline1-oxide

To a solution of 2-(3-chloro-1-oxy-quinolin-6-ylmethyl)-isonicotinicacid (100 mg, 0.32 mmol, 1 eq) in DMF (10 mL) was added5-aminomethyl-4,6-dimethyl-pyridin-2-ylamin (106 mg, 0.48 mmol, 1.5 eq),HATU (182 mg, 0.48 mmol, 1.5 eq), and Et₃N (1 mL). The mixture wasstirred at rt for 3 h. Then it was quenched with water, extracted withDCM. The combined extracts were dried, concentrated, and the residue waspurified by prep-HPLC to give6-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline1-oxide (30 mg, 21%) as a gray solid. LRMS (M+H⁺) m/z calculated 448.1,found 447.8.

¹H NMR (DMSO-d6, 400 MHz) δ 8.74 (d, 1H), 8.59-8.63 (m, 2H), 8.38 (d,1H), 8.10 (s, 1H), 7.91 (s, 1H), 7.73-7.75 (m, 2H), 7.59-7.61 (m, 1H),6.13 (s, 1H), 5.71 (s, 2H), 4.33 (d, 4H), 2.30 (s, 3H), 2.16 (s, 3H).

Example 100: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3,8-dichloroquinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of 2-((3,8-dichloroquinolin-6-yl)methyl)isonicotinicacid

To a solution of methyl2-((3,8-dichloroquinolin-6-yl)methyl)isonicotinate (300 mg, 0.86 mmol, 1eq) in THF (10 mL)/water (5 mL) was added NaOH (42 mg, 1.05 mmol, 1.2eq). The mixture was stirred at rt for 3 h and then aqueous HCl (2N) wasadded to adjust pH 4. The mixture was extracted with EtOAc, and theorganic layer was concentrated under pressure to provide the crudeproduct (170 mg, 59%) without further purification.

Step 2: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3,8-dichloroquinolin-6-yl)methyl)isonicotinamide

To a solution of 2-(3,8-dichloro-quinolin-6-ylmethyl)-isonicotinic acid(80 mg, 0.24 mmol, 1 eq) in DMF (10 mL) was added 5-aminomethyl-4,6-dimethyl-pyridin-2-ylamine (83 mg, 0.36 mmol, 1.5 eq), HATU (110 mg,0.29 mmol, 1.2 eq), and Et₃N (121.2 mg, 1.2 mmol, 5 eq). The mixture wasstirred at rt for 3 h. Then it was quenched with water, extracted withDCM. The combined extracts were dried, concentrated, and the residue waspurified by prep-HPLC to giveN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3,8-dichloroquinolin-6-yl)methyl)isonicotinamide(16 mg, 14%) as a white solid. LRMS (M+H⁺) m/z calculated 466.1, found465.8.

¹H NMR (DMSO-d6, 400 MHz) δ 8.95 (s, 1H), 8.60-8.66 (m, 3H), 7.77-7.94(m, 3H), 8.00 (s, 1H), 7.60 (d, 1H), 7.68-7.71 (m, 1H), 6.18 (s, 1H),5.91 (s, 2H), 4.33-4.34 (m, 4H), 2.32 (s, 3H), 2.19 (s, 3H).

Example 101: Preparation ofN-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3,8-dichloroquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3,8-dichloroquinolin-6-yl)methyl)isonicotinamide(25 mg, 23%) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3,8-dichloroquinolin-6-yl)methyl)isonicotinamide(Example 100) as a white solid. LRMS (M+H⁺) m/z calculated 452.1, found451.8.

¹H NMR (DMSO-d6, 400 MHz) δ 8.94-8.98 (m, 2H), 8.63-8.64 (m, 2H), 7.95(m, 1H), 7.84-7.88 (m, 2H), 7.62 (d, 1H), 6.24-6.26 (m, 1H), 6.80 (s,2H), 4.28-4.36 (m, 4H), 2.28 (s, 3H)

Example 102: Preparation ofN-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-5-fluoroquinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of methyl 5-fluoroquinoline-6-carboxylate and methyl7-fluoroquinoline-6-carboxylate

To a suspension of methyl 4-amino-2-fluorobenzoate (20.0 g, 0.129 mol, 1eq) and p-chloranil (35.0 g, 0.142 mol, 1.1 eq) in 500 mL of 6N HClsolution was added acrolein (13.5 g, 0.194 mol, 1.5 eq, 80% purity). Themixture was stirred at 100° C. for 10 min. After cooling to rt, themixture was basified to pH 3 with sat. NaHCO₃. The precipitate wasremoved by filtration. The filtrate was extracted with CHCl₃. Thecombined organic layers were dried and concentrated. The residue waspurified by chromatography on silica gel column (EtOAc/PE=1/10, v/v) togive methyl 5-fluoroquinoline-6-carboxylate and methyl7-fluoroquinoline-6-carboxylate (3.0 g, 11%) as a yellow solid.

Step 2: Preparation of methyl 3-chloro-5-fluoroquinoline-6-carboxylateand methyl 3-chloro-7-fluoroquinoline-6-carboxylate

To a solution of mixture of methyl 5-fluoroquinoline-6-carboxylate andmethyl 7-fluoroquinoline-6-carboxylate (3.7 g, 18.0 mmol, 1 eq) in DMF(90 mL) was added NCS (7.2 g, 54.0 mmol, 3 eq). The reaction mixture wasstirred at 120° C. for 40 min under N₂. The reaction mixture was allowedto cool to ambient temperature, treated with water, neutralized withsolid NaHCO₃ and stirred at rt for 30 min. Powdered sodium thiosulfatewas carefully added to remove excess of NCS. The mixture was extractedwith EtOAc. The organic layer was dried and concentrated under vacuum.The crude product was purified by flash-chromatography on silica gelcolumn to afford the mixture of methyl3-chloro-5-fluoroquinoline-6-carboxylate and methyl3-chloro-7-fluoroquinoline-6-carboxylate (2.1 g, 49%) as a yellow solid.

Step 3: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-5-fluoroquinolin-6-yl)methyl)isonicotinamide

To a solution of methyl 3-chloro-5-fluoroquinoline-6-carboxylate (104.4mg, 0.32 mmol, 1.0 eq) in THF (5 mL)/H₂O (5 mL) was added LiOH.H₂O(26.87 mg, 0.64 mmol, 2 eq). The mixture was stirred at 40° C. for 1 hand was acidified to pH 5 with 1N HCl solution. The mixture wasconcentrated in vacuo and the residue was directly used without furtherpurification. To a solution of the above crude product in DMF (10 mL)was added 5-aminomethyl-4,6-dimethyl-pyridin-2-ylamin (106 mg, 0.48mmol, 1.5 eq), HATU (182 mg, 0.48 mmol, 1.5 eq), and Et₃N (1 mL). Themixture was stirred at rt for 3 h. Then it was quenched with water,extracted with DCM. The combined extracts were dried, concentrated, andthe residue was purified by prep-HPLC to giveN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-5-fluoroquinolin-6-yl)methyl)isonicotinamide(17 mg, 12.4%) as a white solid. LRMS (M+H⁺) m/z calculated 450.1, found450.1. ¹H NMR (DMSO-d6, 400 MHz) δ 8.87 (d, 1H), 8.55-8.58 (m, 3H), 7.93(d, 1H), 7.73-7.81 (m, 2H), 7.60 (d, 1H), 6.11 (s, 1H), 5.66 (s, 2H),4.33-4.38 (m, 4H), 2.29 (s, 3H), 2.16 (s, 3H).

Example 103: Preparation ofN-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-5-fluoroquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro-5-fluoroquinolin-6-yl)methyl)isonicotinamide(45 mg, 32%) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-5-fluoroquinolin-6-yl)methyl)isonicotinamide(Example 102) as a white solid. LRMS (M+H⁺) m/z calculated 436.1, found436.1. ¹H NMR (DMSO-d6, 400 MHz) δ 8.99 (m, 1H), 8.88 (s, 1H), 8.57 (d,2H), 7.94 (d, 1H), 7.63-7.81 (m, 3H), 7.24 (s, 1H), 6.21 (d, 1H), 5.72(s, 2H), 4.40 (s, 2H), 4.27 (d, 2H), 2.27 (s, 3H).

Example 104: Preparation ofN-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of methyl 3-chloroquinoline-6-carboxylate

To a solution of methyl quinoline-6-carboxylate (15.0 g, 80.2 mmol, 1.0eq) in DMF (200 ml) was added N-chlorosuccinimide (21.4 g, 0.16 mol, 2.0eq) and the reaction mixture was stirred at 120° C. for 20 h. Thereaction mixture was allowed to cool to rt, treated with brine and themixture was extracted with EtOAc. The organic layer was dried overNa₂SO₄, filtered and concentrated under vacuum. The crude product waspurified by chromatography on silica gel (EtOAc/PE=1/8, v/v) to affordmethyl 3-chloroquinoline-6-carboxylate (9.1 g, 51%) as a yellow solid.

Step 2: Preparation of methyl (3-chloro-quinolin-6-yl)-methanol

To a solution of methyl 3-chloroquinoline-6-carboxylate (8 g, 36.0 mmol,1.0 eq) in dry THF was added LiAlH₄ (2.5M in THF, 5.8 mL, 0.4 eq). Theresulting mixture was stirred at 0° C. for 1 h. After which period,additional LiAlH₄ (2.5M in THF, 2.8 mL, 0.2 eq) was added. The systemwas stirred for another 30 min at 0° C. and quenched by the slowaddition of 1N aqueous NaOH. The resulting precipitate was filtered, andthe filtrate was extracted with EtOAc. The combined organic layers weredried and concentrated. The residue was purified by silica gelchromatography (PE/EtOAc=20/1-5/1, v/v) to afford(3-chloro-quinolin-6-yl)-methanol (4.8 g, 69%) as a white solid.

Step 3: Preparation of 3-chloro-6-chloromethyl-quinoline

To (3-chloro-quinolin-6-yl)-methanol (3.3 g, 17.1 mmol, 1.0 eq) wasadded SOCl₂ (50 mL) and the mixture was stirred at rt for 1 h. Thevolatiles were then removed under vacuum and the residue was dissolvedin DCM. The mixture was washed with saturated aq. NaHCO₃, dried andconcentrated to give 3-chloro-6-chloromethyl-quinoline (3.4 g, 94%) as ayellow solid.

Step 4: Preparation of methyl 2-methyl-6-(trimethylstannyl)isonicotinate

Hexamethyldistannane (0.21 mL, 334 mg, 1.02 mmol) andtetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) were addedto a solution of methyl 2-chloro-6-methylisonicotinate (100 mg, 0.54mmol) in dry dioxane mL) and the resulting mixture was refluxed for 3 hunder N₂. EtOAc (50 mL) and water (100 mL) were then added. The layerswere separated and the organic layer was washed with water (5×100 mL),dried (Na₂SO₄), and the solvent removed by rotary evaporation to leavecrude residue which was used in the next step without furtherpurification.

Step 4: Preparation of methyl2-((3-chloroquinolin-6-yl)methyl)-6-methylisonicotinate

To a solution of 3-chloro-6-chloromethyl-quinoline (110 mg, 0.52 mmol,1.0 eq) and crude methyl 2-methyl-6-(trimethylstannyl)isonicotinate indioxane (10 mL) Pd(PPh₃)₂Cl₂ (36 mg, 0.05 mmol, 0.1 eq). The mixture wasstirred at 90° C. for 3 h under nitrogen atmosphere, stripped of solventand purified by silica gel chromatography (EtOAc/PE=10/1-5:1, v/v) toafford methyl 2-((3-chloroquinolin-6-yl)methyl)-6-methylisonicotinate(70 mg, 40%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (d,1H), 8.53 (d, 1H), 7.98 (d, 1H), 7.85 (d, 1H), 7.73 (dd, 1H), 7.58 (s,1H), 7.57 (s, 1H), 4.36 (s, 2H), 3.85 (s, 3H), 2.53 (s, 3H).

Step 5: Preparation of2-((3-chloroquinolin-6-yl)methyl)-6-methylisonicotinic acid

To a solution of 2-((3-chloroquinolin-6-yl)methyl)-6-methylisonicotinate(70 mg, 0.21 mmol, 1.0 eq.) in THF/H₂O (5 mL/1 mL) was added LiOH (71mg, 2.1 mmol, 10 eq.). The resulting mixture was stirred for 1 h at roomtemperature; all starting material had been consumed (assessed by TLC).Volatile solvent was removed on rotavap, the aqueous residue wasneutralized with 1M HCl and extracted with EtOAc (10 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated to furnish crude acid (50 mg, 75%), which was used directlyin the next step without further purification.

Step 6: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-6-methylisonicotinamide

To a solution of 2-((3-chloroquinolin-6-yl)methyl)-6-methylisonicotinicacid (50 mg, 0.16 mmol, 1.0 eq.) in DMF (5 mL) was added5-aminomethyl-6-methyl-pyridin-2-ylamine hydrochloride (33 mg, 0.0.19mmol, 1.2 eq.) followed by HATU (91 mg, 0.24 mmol, 1.5 eq.) and DIPEA(0.08 mL, 0.48 mmol, 3.0 eq.) at 0° C. The reaction mixture was allowedto warm to room temperature and stirred for 2 h under N₂. Water (20 mL)was added, and the mixture was extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by prep-TLC(DCM:MeOH=15:1) to give N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-6-methylisonicotinamide (24mg, 34%) as a yellow solid. LRMS (M+H⁺) m/z calculated 446.2, found446.2. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.83 (d, 1H), 8.66 (s, 1H), 8.53 (d,1H), 7.97 (d, 1H), 7.84 (d, 1H), 7.71 (dd, 1H), 7.50 (s, 1H), 7.47 (s,1H), 6.32 (s, 2H), 4.32 (d, 2H), 4.29 (s, 2H), 2.48 (s, 3H), 2.37 (s,3H), 2.23 (s, 3H).

Example 105: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-chloro-1H-indazol-1-yl)methyl)isonicotinamide

Step 1: Preparation of methyl 3-chloroquinoline-6-carboxylate

To a solution of methyl isonicotinate (5.0 g, 36.5 mmol, 1.0 eq) in MeOH(70 ml) was added conc. H₂SO₄ (300 mg, 3.1 mmol, 0.086 eq) dropwise atrt. The above mixture was heated at reflux, to which was added anaqueous solution of (NH₄)₂S₂O₈ (15.0 g, 65.7 mmol in 30 mL of water)dropwise. The reaction mixture was kept at reflux for additional 30minutes, cooled to rt, treated with 4M NaOH and aqueous NaHCO₃ to aboutpH 7. The aqueous mixture was concentrated under vacuum, and the residuewas extracted with EtOAc (100 mL×2). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated undervacuum. The crude product was purified by chromatography on silica gel(PE/EtOAc=1/3 to 1/1, v/v) to afford methyl3-chloroquinoline-6-carboxylate (1.5 g, 25%) as a white solid. LCMS(M+H⁺) m/z calculated 168, found 168.0. ¹H NMR (CDCl₃, 400 MHz): δ 8.71(d, J=4.8 Hz, 1H), 7.84 (d, J=0.8 Hz, 1H), 7.77 (dd, 1H), 4.84 (s, 2H),3.96 (s, 3H).

Step 2: Preparation of methyl2-(((methylsulfonyl)oxy)methyl)isonicotinate

To a stirred solution of methyl 2-(hydroxymethyl)isonicotinate (1.0 g,6.0 mmol, 1.0 eq) and TEA (1.2 g, 12.0 mmol, 2.0 eq) in DCM (15 mL) wasadded MsCl (755 g, 6.6 mmol, 1.1 eq) at 0° C. The resulting mixture wasstirred at rt for a further 30 minutes, diluted with DCM (60 mL), washedwith water (30 mL), brine (30 mL×2), dried and concentrated to affordmethyl 2-(((methylsulfonyl)oxy)methyl)isonicotinate (1.2 g, 82%) as adark brown oil.

Step 3: Preparation of methyl2-((5-chloro-1H-indazol-1-yl)methyl)isonicotinate

A mixture of methyl 2-(((methylsulfonyl)oxy)methyl)isonicotinate (300mg, 1.22 mmol, 1.0 eq), 5-chloro-1H-indazole (280 mg, 1.84 mmol, 1.5 eq)and K₂CO₃ (337 mg, 2.44 mmol, 2 eq) in DMF (5 mL) was stirred at 70° C.for 2 hours. The mixture was cooled to rt, diluted with EtOAc (50 mL),washed with water (30 mL), brine (30 mL×2), dried and concentrated. Theresidue was purified by chromatography on silica gel (PE/EtOAc=10/1-5/1v/v) to afford methyl 2-((5-chloro-1H-indazol-1-yl)methyl)isonicotinate(120 mg, 33%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.68 (d,1H,), 8.00 (s, 1H), 7.73 (d, 1H), 7.69 (d, 1H), 7.48 (s, 1H), 7.34 (d,1H), 7.28 (dd, 1H), 5.73 (s, 2H), 3.85 (s, 3H). Chromatography on silicagel (PE/EtOAc=5/1 to 3/1, v/v) to afford methyl2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinate (70 mg, 19%) as awhite solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.73 (d, 1H), 8.05 (s, 1H), 7.79(dd, 1H), 7.72 (s, 1H), 7.64-7.60 (m, 2H), 7.21 (dd, 1H), 5.75 (s, 2H),3.90 (s, 3H).

Step 4: Preparation of 2-((5-chloro-1H-indazol-1-yl)methyl)isonicotinicacid

To a solution of methyl2-((5-chloro-1H-indazol-1-yl)methyl)isonicotinate (270 mg, 0.89 mmol,1.0 eq) in THF (5 mL) was added LiOH.H₂O (375 mg, 8.9 mmol, 10.0 eq) andwater (5 mL). The mixture was stirred at rt for 2 hours, concentratedunder vacuum to remove most THF. The aqueous mixture was adjusted with1M HCl to about pH 7. The white suspension was filtered and the solidwas washed with water (10 mL), evaporated under vacuum to dryness toafford 2-((5-chloro-1H-indazol-1-yl)methyl)isonicotinic acid (240 mg,93%) as a white solid.

Step 5: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-chloro-1H-indazol-1-yl)methyl)isonicotinamide

To a stirred mixture of 2-((5-chloro-1H-indazol-1-yl)methyl)isonicotinicacid (100 mg, 0.35 mmol, 1.0 eq), TEA (101 mg, 1.0 mmol, 3.0 eq) and5-(aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride (65 mg, 0.35mmol, 1.0 eq) in DMF (3 mL) was added HATU (264 mg, 0.7 mmol, 2.0 eq) at0° C. The reaction mixture was stirred at rt for 16 h, and then dilutedwith EtOAc (50 mL). The new mixture was washed with water (30 mL), brine(30 mL×2), dried and concentrated. The residue was purified bychromatography on silica gel (DCM/MeOH=50/1 to 20/1, v/v) and thenPrep-TLC (DCM/MeOH=20/1, v/v) to affordN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-chloro-1H-indazol-1-yl)methyl)isonicotinamide(10 mg, 7%) as a white solid. LCMS (M+H⁺) m/z calculated 421, found421.0.

¹H NMR (DMSO-d₆, 400 MHz): δ 8.68 (t, 1H), 8.57 (d, 1H), 8.10 (d, 1H),7.88 (d, 1H), 7.75 (d, 1H), 7.65 (dd, 1H), 7.49 (s, 1H), 7.40 (dd, 1H),6.14 (s, 1H), 5.82-5.73 (m, 4H), 4.30 (d, 2H), 2.28 (s, 3H), 2.15 (s,3H). LRMS (M+H⁺) m/z calculated 421.2, found 421.0.

Example 106: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinamide

Step 1: Preparation of 2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinicacid

To a solution of methyl 2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinate (150 mg, 0.50 mmol, 1.0 eq) in THF (5 mL) was addedLiOH H₂O (208 mg, 5.0 mmol, 10.0 eq) and water (5 mL). The mixture wasstirred at rt for 2 hours, concentrated under vacuum to remove most THF.The aqueous mixture was adjusted with 1M HCl to pH˜7. The whitesuspension was filtered and the solid was washed with water (10 mL),concentrated to afford 2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinicacid (110 mg, 77%) as a white solid.

Step 2: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinamide

To a stirred mixture of 2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinicacid (110 mg, 0.38 mmol, 1.0 eq), TEA (105 mg, 1.0 mmol, 3.0 eq) and5-(aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride (71 mg, 0.38mmol, 1.0 eq) in DMF (3 mL) was added HATU (290 mg, 0.76 mmol, 2.0 eq)at 0° C. The reaction mixture was stirred at rt for 16 h, and thendiluted with EtOAc (50 mL). The new mixture was washed with water (30mL), brine (30 mL×2), dried and concentrated. The residue was purifiedby chromatography on silica gel (DCM/MeOH=50/1 to 10/1, v/v) and thenPrep-TLC (DCM/MeOH=10/1, v/v) to affordN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinamide(30 mg, 19%) as a white solid. LCMS (M+H⁺) m/z calculated 421.2, found421.0.

¹H NMR (DMSO-d₆, 400 MHz): δ 8.84 (s, 1H), 8.65 (d, 1H), 8.55 (d, 1H),7.85 (dd, 1H), 7.69 (dd, 1H), 7.60-7.63 (m, 2H), 7.23 (dd, 1H), 6.38 (s,1H), 5.81 (s, 2H), 4.33 (d, 2H), 2.41 (s, 3H), 2.27 (s, 3H).

Example 107: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-methyl-2H-indazol-2-yl)methyl)isonicotinamide

Step 1: Preparation of methyl2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinate

Methyl 2-((5-methyl-2H-indazol-2-yl)methyl)isonicotinate and methyl2-((5-methyl-1H-indazol-1-yl)methyl)isonicotinate were prepared asdescribed for methyl 2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinate.

¹H NMR (CDCl₃, 400 MHz): δ 8.72 (d, 1H), 7.98 (s, 1H), 7.77 (dd, 1H),7.67 (s, 1H), 7.61 (d, 1H), 7.39 (s, 1H), 7.12 (dd, 1H), 5.75 (s, 2H),3.88 (s, 3H), 2.40 (s, 3H). Methyl2-((5-methyl-1H-indazol-1-yl)methyl)isonicotinate: ¹H NMR (CDCl₃, 400MHz): δ 8.72 (d, 1H), 8.00 (s, 1H), 7.72 (d, 1H), 7.51 (s, 1H), 7.47 (s,1H), 7.29 (d, 1H), 7.18 (d, 1H), 5.76 (s, 2H), 3.84 (s, 3H), 2.43 (s,3H).

Step 2: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-methyl-2H-indazol-2-yl)methyl)isonicotinamidewas prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-chloro-2H-indazol-2-yl)methyl)isonicotinamide.LCMS (M+H+) m/z calculated 401.2, found 401.0. 1H NMR (DMSO-d6, 400MHz): δ 8.78 (s, 1H), 8.63 (d, 1H), 8.38 (s, 1H), 7.75-7.64 (m, 1H),7.54 (s, 1H), 7.47 (d, 1H), 7.46 (s, 1H), 7.07 (dd, 1H), 6.29 (s, 2H),5.75 (s, 2H), 4.32 (d, 2H), 2.35 (s, 6H), 2.22 (s, 3H).

Example 108: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-methyl-3a,7a-dihydro-1H-indazol-1-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-methyl-3a,7a-dihydro-1H-indazol-1-yl)methyl)isonicotinamidewas prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5-chloro-1H-indazol-1-yl)methyl)isonicotinamide(Example 105). LCMS (M+H⁺) m/z calculated 401.2, found 401.0. ¹H NMR(DMSO-d₆, 400 MHz): δ 8.68 (t, 1H), 8.59 (d, 1H), 8.01 (d, 1H), 7.63(dd, 1H), 7.54 (d, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.26-7.13 (m, 1H),6.16 (s, 1H), 5.87 (s, 2H), 5.75 (s, 2H), 4.29 (d, 2H), 2.40 (s, 3H),2.29 (s, 3H), 2.15 (s, 3H).

Example 109: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-methyl-2-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-methyl-2-(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide(19 mg, 13% yields for 2 steps) was prepared as described forN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(Example 15) as purple solid. LRMS (M+H⁺) m/z calculated 537.1, found537.1. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.40 (s, 1H), 9.27-9.24 (t, 1H),8.63-8.62 (d, 1H), 8.31 (s, 1H), 8.02-8.00 (d, 1H), 7.82 (s, 1H),7.75-7.45 (m, 5H), 7.24-7.21 (d, 1H), 4.78 (s, 2H), 4.60-4.58 (d, 2H),3.52 (s, 3H), 2.52-2.51 (t, 3H).

Example 110: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide(16 mg, 15%) was prepared as described in Example 24, Step 7 as a yellowsolid. LRMS (M+H⁺) m/z calculated 459.1, found 459.1. ¹H NMR (DMSO-d₆,300 MHz) δ 11.39 (s, 1H), 9.24 (t, 1H), 8.66-8.64 (d, 1H), 8.18-8.16 (d,1H), 7.85-7.78 (m, 3H), 7.65-7.62 (m, 2H), 7.50-7.36 (m, 3H), 7.24-7.20(d, 1H), 4.59-4.57 (d, 2H), 4.33 (s, 2H), 2.62 (s, 3H).

Example 111: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide(30 mg, 20% yield for 2 steps) was prepared as described forN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(Example 142). LRMS (M+H⁺) m/z calculated 434.2, found 434.2. ¹H NMR(CD₃OD, 300 MHz) δ 8.64 (d, 1H), 8.14 (d, 1H), 8.06 (d, 1H), 7.88 (d,1H), 7.77-7.59 (m, 6H), 7.47 (d, 1H), 7.37 (d, 1H), 6.90 (d, 1H), 4.69(s, 2H), 4.38 (s, 2H), 2.68 (s, 3H).

Example 112: Preparation ofN-((6-amino-2-methylpyridin-3-yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide(29 mg, 14%) was prepared as described in Example 24, Step 7 as a yellowsolid. LRMS (M+H⁺) m/z calculated 398.1, found 398.1. ¹H NMR (DMSO-d₆,400 MHz) δ 9.02 (t, 1H), 8.65-8.63 (d, 1H), 8.18-8.16 (d, 1H), 7.86-7.63(m, 5H), 7.38-7.36 (d, 2H), 7.26-7.24 (d, 1H), 6.25-6.23 (d, 1H),5.77-5.76 (d, 2H), 4.33-4.29 (m, 4H), 2.63 (s, 3H), 2.23 (s, 3H).

Example 113: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide(45 mg, 16%) was prepared as described in Example 24, Step 7. LRMS(M+H⁺) m/z calculated 411.9, found 411.9. ¹H NMR (DMSO-d₆, 300 MHz) δ8.59-8.65 (m, 2H), 8.17 (d, 1H), 7.83 (d, 1H), 7.75 (d, 2H), 7.58-7.64(m, 2H), 7.37 (d, 1H), 6.11 (s, 1H), 5.67 (s, 2H), 4.30-4.34 (m, 3H),2.61 (d, 3H), 2.29 (s, 3H), 2.15 (s, 3H).

Example 114: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamide(29 mg, 21%) was prepared as described in Example 24, Step 7 as a yellowsolid. LRMS (M+H⁺) m/z calculated 412.1, found 412.1. ¹H NMR (DMSO-d₆,400 MHz) δ 8.72 (s, 1H), 8.57-8.52 (d, 2H), 8.00 (s, 1H), 7.80-7.58 (m,2H), 7.53-7.44 (m, 3H), 6.05 (s, 1H), 5.62 (s, 2H), 4.26 (s, 4H),2.42-2.39 (m, 3H), 2.22 (s, 3H), 2.07 (s, 3H).

Example 115: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamide(27 mg, 18% yield for 2 steps) was prepared as described forN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(Example 142). LRMS (M+H⁺) m/z calculated 434.2, found 434.2. ¹H NMR(CD₃OD, 400 MHz) δ 8.74 (d, 1H), 8.66 (d, 1H), 8.11 (s, 1H), 8.07 (d,1H), 7.88 (d, 1H), 7.83 (s, 1H), 7.72 (d, 1H), 7.69 (d, 1H), 7.61 (s,2H), 7.51 (d, 1H), 7.49 (d, 1H), 6.92 (d, 1H), 4.71 (s, 2H), 4.41 (s,2H), 2.51 (s, 3H).

Example 116: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-methyl quinolin-3-yl)methyl)isonicotinamide (62 mg, 40%) was prepared as described in Example24, Step 7 as an off-white solid. LRMS (M+H⁺) m/z calculated 459, found459. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.39 (s, 1H), 9.24 (t, 1H), 8.80 (s,1H), 8.64 (d, 1H), 8.09 (s, 1H), 7.87 (d, 1H), 7.81 (s, 1H), 7.65-7.67(m, 2H), 7.50-7.55 (m, 2H), 7.45 (d, 1H), 7.23 (d, 1H), 4.59 (d, 2H),4.37 (s, 2H), 2.48 (s, 3H).

Example 117: Preparation ofN-((6-amino-2-methylpyridin-3-yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamide

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamidewas prepared as described in Example 24, Step 7.

Example 118: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide(30 mg, 20% yield for 2 steps) was prepared as described forN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(Example 142). LRMS (M+H⁺) m/z calculated 438.2, found 438.2. ¹H NMR(CD₃OD, 300 MHz) δ 8.81 (d, 1H), 8.66 (d, 1H), 8.20 (d, 1H), 8.08 (d,1H), 8.05 (dd, 1H), 7.83 (s, 1H), 7.71 (d, 1H), 7.70 (d, 1H), 7.62 (s,1H), 7.57-7.47 (m, 3H), 6.93 (d, 1H), 4.72 (s, 2H), 4.44 (s, 2H).

Example 119: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide(35 mg, 25%) was prepared as described in Example 24, Step 7 as anoff-white solid. LRMS (M+H⁺) m/z calculated 416.1, found 416.1. ¹H NMR(DMSO-d₆, 300 MHz) δ 8.87-8.86 (d, 1H), 8.66-8.58 (m, 2H), 8.18 (d, 1H),8.06-8.02 (m, 1H), 7.78-7.72 (m, 2H), 7.64-7.58 (m, 2H), 6.11 (s, 2H),5.68 (s, 2H), 4.36-4.33 (m, 4H), 2.30 (s, 3H), 2.16 (s, 3H).

Example 120: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide(42 mg, 26.8%) was prepared as described in Example 24, Step 7. LRMS(M+H⁺) m/z calculated 463.1, found 463.1. ¹H NMR (DMSO-d₆, 300 MHz) δ11.41 (s, 1H), 9.26 (t, 1H), 8.88 (d, 1H), 8.65 (d, 1H), 8.10 (s, 1H),8.02-8.07 (m, 1H), 7.82 (s, 1H), 7.74 (dd, 1H), 7.61-7.67 (m, 2H), 7.51(s, 1H), 7.45 (d, 1H), 7.22 (d, 1H), 4.59 (d, 2H), 4.39 (s, 2H).

Example 121: Preparation ofN-((6-amino-2-methylpyridin-3-yl)methyl)-2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide

N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((6-fluoroquinolin-3-yl)methyl)isonicotinamide(18 mg, 13.2%) was prepared as described in Example 24, Step 7. LRMS(M+H⁺) m/z calculated 401.9, found 401.9. ¹H NMR (CD₃OD, 300 MHz) δ 8.80(d, 1H), 8.63 (d, 1H), 8.20 (s, 1H), 8.01-8.04 (m, 1H), 7.78 (s, 1H),7.63-7.64 (m, 1H), 7.52-7.58 (m, 3H), 7.40 (d, 1H), 4.43 (d, 4H), 2.38(s, 3H).

Example 122: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((7-fluoroquinolin-3-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((7-fluoroquinolin-3-yl)methyl)isonicotinamide(35 mg, 25%) was prepared as described in Example 24, Step 7. LRMS(M+H⁺) m/z calculated 415.9, found 415.9. ¹H NMR (DMSO-d₆, 300 MHz) δ8.92 (d, 1H), 8.65 (t, 1H), 8.60 (d, 1H), 8.26 (s, 1H), 8.04 (dd, 1H),7.79 (s, 1H), 7.73 (dd, 1H), 7.61 (d, 1H), 7.51-7.55 (m, 1H), 6.13 (s,1H), 5.68 (s, 2H), 4.35-4.37 (m, 4H), 2.31 (s, 3H), 2.17 (s, 3H).

Example 123: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((7-fluoroquinolin-3-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((7-fluoroquinolin-3-yl)methyl)isonicotinamide(45 mg, 28.7%) was prepared as described in Example 24, Step 7. LRMS(M+H⁺) m/z calculated 462.8, found 462.8. ¹H NMR (DMSO-d₆, 300 MHz) δ11.39-11.42 (m, 1H), 9.26 (t, 1H), 8.92 (s, 1H), 8.64 (d, 1H), 8.27 (s,1H), 8.04 (dd, 1H), 7.82 (s, 1H), 7.65-7.74 (m, 2H), 7.43-7.55 (m, 3H),7.22 (d, 1H), 4.59 (d, 2H), 4.38 (s, 2H).

Example 124: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((7-fluoroquinolin-3-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((7-fluoroquinolin-3-yl)methyl)isonicotinamide(16 mg, 10.8%) was prepared as described forN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(Example 142). LRMS (M+H⁺) m/z calculated 437.8, found 437.8. ¹H NMR(CD₃OD, 400 MHz) δ 8.72 (d, 1H), 8.52 (d, 1H), 8.09 (s, 1H), 7.93 (d,1H), 7.77-7.80 (m, 1H), 7.70 (s, 1H), 7.56-7.58 (m, 2H), 7.47-7.50 (m,2H), 7.35 (d, 2H), 7.26-7.31 (m, 1H), 6.78 (d, 1H), 4.58 (s, 2H), 4.29(s, 2H).

Example 125: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-(quinolin-3-ylmethyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-(quinolin-3-ylmethyl)isonicotinamide(24 mg, 17%) was prepared as described in Example 24, Step 7 as a yellowsolid. LRMS (M+H⁺) m/z calculated 445.1, found 445.1. ¹H NMR (DMSO-d₆,400 MHz) δ 11.40 (s, 1H), 9.26 (t, 1H), 9.01 (s, 1H), 8.66-8.65 (d, 1H),8.40 (s, 1H), 8.05-8.00 (t, 2H), 7.85 (s, 1H), 7.80 (t, 1H), 7.69-7.66(m, 2H), 7.51-7.44 (m, 2H), 7.24-7.21 (d, 1H), 4.60-4.59 (d, 2H), 4.44(s, 2H).

Example 126: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-chloroquinolin-3-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6-chloroquinolin-3-yl)methyl) isonicotinamide (12 mg, 15%) was prepared asdescribed in Example 24, Step 7 as an off-white solid. LRMS (M+H⁺) m/zcalculated 479, found 479. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.39 (s, 1H),9.25 (t, 1H), 8.92 (d, 1H), 8.64 (d, 1H), 8.20 (s, 1H), 8.08 (d, 1H),8.00 (d, 1H), 7.82 (s, 1H), 7.71 (d, 1H), 7.66 (d, 2H), 7.50 (d, 2H),7.45 (d, 1H), 7.22 (d, 1H), 4.59 (d, 2H), 4.40 (s, 2H).

Example 127: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((2-methylquinolin-7-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((2-methylquinolin-7-yl)methyl)isonicotinamide(35 mg, 22%) was prepared as described forN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(Example 142). LRMS (M+H⁺) m/z calculated 434, found 434. ¹H NMR(DMSO-d₆, 400 MHz) δ 9.39 (t, 1H), 8.67 (d, 1H), 8.18 (d, 1H), 8.13 (d,1H), 7.80-7.85 (m, 3H), 7.75 (d, 1H), 7.68 (d, 1H), 7.54 (s, 1H), 7.47(d, 1H), 7.35-7.40 (m, 2H), 6.84 (d, 1H), 6.72 (s, 2H), 4.60 (d, 2H),4.37 (s, 2H), 2.62 (s, 3H).

Example 128: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2-methylquinolin-7-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2-methylquinolin-7-yl)methyl)isonicotinamide(25 mg, 15%) was prepared as described in Example 24, Step 7. LRMS(M+H+) m/z calculated 459, found 459. ¹H NMR (DMSO-d₆, 300 MHz) δ 11.40(br, 1H), 9.26 (t, 1H), 8.65 (d, 1H), 8.17 (d, 1H), 7.79-7.84 (m, 3H),7.65 (d, 1H), 7.42-7.50 (m, 3H), 7.35 (d, 1H), 7.22 (d, 2H), 4.57 (d,2H), 4.35 (s, 2H), 2.62 (s, 3H).

Example 129: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2-methylquinolin-7-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2-methylquinolin-7-yl)methyl)isonicotinamide(10 mg, 7%) was prepared as described in Example 24, Step 7. LRMS (M+H⁺)m/z calculated 412, found 412. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.59-8.64 (m,2H), 8.17 (d, 1H), 7.82 (d, 1H), 7.76 (d, 2H), 7.60 (d, 1H), 7.45 (d,1H), 7.35 (d, 1H), 6.10 (s, 1H), 5.67 (s, 2H), 4.33 (s, 4H), 2.62 (s,3H), 2.29 (s, 3H), 2.15 (s, 3H).

Example 130: Preparation ofN-(3-chloro-6-fluoro-1H-indol-5-ylmethyl)-2-(2-cyano-quinolin-6-ylmethyl)-isonicotinamide

N-(3-chloro-6-fluoro-1H-indol-5-ylmethyl)-2-(2-cyano-quinolin-6-ylmethyl)-isonicotinamide(90 mg, 22%) was prepared as described in Example 24, Step 7. LRMS(M+H⁺) m/z calculated 570.1, found 570.1. ¹H NMR (DMSO-d₆, 400 MHz) δ11.41 (s, 1H), 9.26 (t, 1H), 8.60-8.65 (m, 2H), 8.00-8.08 (m, 3H),7.87-7.89 (dd, 1H), 7.81 (s, 1H), 7.66-7.67 (dd, 1H), 7.50-7.51 (d, 1H),7.43-7.45 (d, 1H), 7.21-7.24 (d, 1H), 4.58-4.59 (d, 2H), 4.42 (s, 2H).

Example 131: Preparation ofN-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(2-cyano-quinolin-6-ylmethyl)-isonicotinamide

N-(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-2-(2-cyano-quinolin-6-ylmethyl)-isonicotinamide(90 mg, 26%) was prepared as described in Example 24, Step 7. LRMS(M+H⁺) m/z calculated 423.1, found 423.1. ¹H NMR (DMSO-d₆, 400 MHz) δ8.60-8.64 (m, 3H), 8.00-8.07 (m, 3H), 7.86-7.88 (m, 1H), 7.78 (s, 1H),7.61-7.62 (d, 1H), 6.12 (s, 1H), 5.68 (s, 2H), 4.33-4.40 (m, 4H), 2.30(s, 3H), 2.16 (s, 3H).

Example 132: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylisoquinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of 6-bromo-3-methyl-isoquinoline

To a solution of 4-bromo-benzylamine (10.0 g, 54 mmol, 1.0 eq) in DCE(100 mL) was added 1,1-dimethoxy-propan-2-one (7.0 g, 59 mmol, 1.1 eq)and MgSO₄ (20 g). The mixture was stirred at 40° C. overnight. Then tothe mixture was added NaBH₃CN (4.08 g, 64.8 mmol, 1.2 eq). Afterstirring at rt for 5 h the mixture was filtered. The filtrate wasconcentrated to give a yellow oil. Chlorosulfonic acid (30 mL) wascooled to −10° C. and the above crude product was added dropwise. Thereaction mixture was heated to 100° C. for 10 min, then cooled andpoured into ice. The mixture was neutralized with 2M NaOH and extractedwith EtOAc. The combined extracts were dried and concentrated. Theresidue was purified by silica gel chromatography (PE/EtOAc=2/1, v/v) toafford 6-bromo-3-methyl-isoquinoline (4.0 g, 34% yield for 3 steps) as ayellow solid.

Step 2: Preparation of methyl 3-methylisoquinoline-6-carboxylate

An autoclave vessel was charged with 6-bromo-3-methyl-isoquinoline (4.0g, 18 mmol), Pd(dppf)Cl₂ (735 mg, 0.9 mmol, 0.05 eq) and triethylamine(5.0 mL, 36 mmol, 2 eq) in 40 mL of methanol. The vessel was purged withnitrogen three times and carbon monoxide three times. The vessel waspressurized to 3 MPa with carbon monoxide and heated to 100° C. Thereaction was thus stirred overnight, then allowed to cool to roomtemperature. The resulting solution was concentrated and purified byflash chromatography on silica gel (PE/EtOAc=1/1, v/v) to afford methyl3-methylisoquinoline-6-carboxylate (3.4 g, 94%) as a white solid.

Step 3: Preparation of (3-methyl-isoquinolin-6-yl)-methanol

To a solution of methyl 3-methylisoquinoline-6-carboxylate (3.3 g, 16.42mmol, 1 eq) in dry THF (100 mL) was added LiAlH(t-BuO)₃ (12.5 g, 45.25mmol, 3 eq). The resulting mixture was stirred at 60° C. for 5 h andthen quenched by the addition of water. The mixture was extracted withEtOAc. The combined extracts were dried and concentrated. The residuewas purified by silica gel chromatography (PE/EtOAc=1/1, v/v) to afford(3-methyl-isoquinolin-6-yl)-methanol (2.5 g, 89%) as a white solid.

Step 4: Preparation of 6-chloromethyl-3-methyl-isoquinoline

To (3-methyl-isoquinolin-6-yl)-methanol (1.5 g, 8.67 mmol, 1 eq) wasadded SOCl₂ (9 mL) and the mixture was stirred at rt for 3 h. Thevolatiles were then removed at 40° C. under vacuum and the residue wasdissolved in DCM. The mixture was washed with saturated aq. NaHCO₃,dried and concentrated to give 6-chloromethyl-3-methyl-isoquinoline (1.4g, 85%) as a white solid.

Step 5: Preparation of methyl2-((3-methylisoquinolin-6-yl)methyl)isonicotinate

Methyl 2-((3-methylisoquinolin-6-yl)methyl)isonicotinate (1.0 g, 47%)was prepared as described for Example 24, Step 5.

Step 6: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylisoquinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylisoquinolin-6-yl)methyl)isonicotinamide(20 mg, 14% yield for 2 steps) was prepared as described forN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(Example 142). LRMS (M+H⁺) m/z calculated 434.2, found 434.2. ¹H NMR(CD₃OD, 400 MHz) δ 9.06 (s, 1H), 8.66 (d, 1H), 8.08 (d, 1H), 7.97 (d,1H), 7.80 (s, 1H), 7.71 (s, 2H), 7.70 (s, 1H), 7.62 (s, 1H), 7.56 (s,1H), 7.50 (d, 1H), 7.47 (d, 1H), 6.92 (d, 1H), 4.71 (s, 2H), 4.11 (s,2H), 2.64 (s, 3H).

Example 133: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-methylisoquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-methylisoquinolin-6-yl)methyl)isonicotinamide(43 mg, 28% yield for 2 steps) was prepared as described for Example132. LRMS (M+H⁺) m/z calculated 459.1, found 459.1. ¹H NMR (DMSO-d₆, 400MHz) δ 11.42 (s, 1H), 9.26 (t, 1H), 9.15 (s, 1H), 8.67 (d, 1H), 8.00(dd, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.67 (d, 1H), 7.58 (s, 1H), 7.53(d, 1H), 7.52 (s, 1H), 7.46 (d, 1H), 7.24 (d, 1H), 4.60 (d, 2H), 4.36(s, 2H), 2.59 (s, 3H).

Example 134: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((2-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((2-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(34 mg, 34% yield for 2 steps) was prepared as described forN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(Example 142). LRMS (M+H⁺) m/z calculated 498.2, found 498.2. ¹H NMR(CD₃OD, 400 MHz) δ 8.66 (d, 1H), 8.49 (d, 1H), 8.06 (d, 1H), 8.03 (d,1H), 8.02 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 7.78 (d, 1H), 7.69 (d,1H), 7.67 (d, 1H), 7.59 (s, 1H), 7.46 (d, 1H), 6.88 (d, 1H), 4.69 (s,2H), 4.43 (s, 2H), 3.37 (s, 3H).

Example 135: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide(24 mg, 23%) was prepared as described in Example 24, Step 7. LRMS(M+H⁺) m/z calculated 523.1, found 523.1. ¹H NMR (CD₃OD, 400 MHz) δ 8.53(d, 1H), 8.47 (d, 1H), 8.02 (d, 1H), 7.99 (d, 1H), 7.84 (s, 1H), 7.75(d, 1H), 7.68 (s, 1H), 7.56 (d, 1H), 7.40 (d, 1H), 7.13 (s, 1H), 7.02(s, 1H), 4.58 (s, 2H), 4.36 (s, 2H), 3.25 (s, 3H).

Example 136: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((4-cyanoquinolin-6-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((4-cyanoquinolin-6-yl)methyl)isonicotinamide(43 mg, 29% yield for 2 steps) was prepared as described forN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(Example 142). LRMS (M+H⁺) m/z calculated 445.2, found 445.2. ¹H NMR(CD₃OD, 300 MHz) δ 9.40 (t, 1H), 9.06 (d, 1H), 8.69 (d, 1H), 8.15-8.11(m, 3H), 8.06 (s, 1H), 7.92 (d, 1H), 7.87 (s, 1H), 7.77 (d, 1H), 7.71(d, 1H), 7.56 (s, 1H), 7.41 (d, 1H), 6.85 (d, 1H), 6.73 (s, 2H), 4.62(d, 2H), 4.50 (s, 2H).

Example 137: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((4-cyanoquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((4-cyanoquinolin-6-yl)methyl)isonicotinamide(45 mg, 29%) was prepared as described in Example 24, Step 7 as a yellowsolid. LRMS (M+H⁺) m/z calculated 470.1, found 470.1. ¹H NMR (DMSO, 400MHz) δ 11.42 (s, 1H), 9.28 (t, 1H), 9.07 (d, 1H), 8.68 (d, 1H), 8.14 (d,1H), 8.12 (s, 1H), 8.06 (s, 1H), 7.91 (d, 1H), 7.86 (s, 1H), 7.68 (d,1H), 7.51 (d, 1H), 7.46 (d, 1H), 7.24 (d, 1H), 4.60 (d, 1H), 4.49 (s,2H).

Example 138: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((4-cyanoquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((4-cyanoquinolin-6-yl)methyl)isonicotinamide(23 mg, 17% yield) was prepared as described in Example 24, Step 7 as ayellow solid. LRMS (M+H⁺) m/z calculated 423.2, found 423.2. ¹H NMR(CD₃OD, 300 MHz) δ 8.98 (d, 1H), 8.63 (d, 1H), 8.10 (d, 1H), 8.07 (s,1H), 7.93 (d, 1H), 7.86 (dd, 1H), 7.77 (s, 1H), 7.63 (dd, 1H), 6.29 (s,1H), 4.50 (s, 2H), 4.49 (s, 2H), 2.38 (s, 3H), 2.26 (s, 3H).

Example 139: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((7-chloroquinolin-3-yl)methyl)isonicotinamide

N-((1-aminoisoquinolin-6-yl)methyl)-2-((7-chloroquinolin-3-yl)methyl)isonicotinamide(34 mg, 23% yields for 2 steps) was prepared as described forN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide (Example 142). LRMS (M+H⁺) m/z calculated 454.1, found454.1. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.42 (d, 1H), 8.96 (s, 1H), 8.68 (d,1H), 8.20 (s, 1H), 8.15 (d, 1H), 8.05 (s, 1H), 8.02 (d, 1H), 7.86 (s,1H), 7.78 (d, 1H), 7.70 (d, 1H), 7.63 (dd, 1H), 7.56 (s, 1H), 7.42 (d,1H), 6.86 (d, 1H), 4.63 (d, 2H), 4.42 (s, 2H).

Example 140: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((7-chloroquinolin-3-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((7-chloroquinolin-3-yl)methyl)isonicotinamide(35 mg, 23%) was prepared as described in Example 24, Step 7 as a whitesolid. LRMS (M+H⁺) m/z calculated 479.1, found 479.1. ¹H NMR (DMSO-d₆,400 MHz) δ 11.42 (s, 1H), 9.27 (t, 1H), 8.95 (d, 1H), 8.66 (d, 1H), 8.27(s, 1H), 8.04 (d, 1H), 8.01 (d, 1H), 7.83 (s, 1H), 7.67 (d, 1H), 7.62(dd, 1H), 7.52 (d, 1H), 7.46 (d, 1H), 7.25 (d, 1H), 4.60 (d, 2H), 4.40(s, 2H).

Example 141: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((7-chloroquinolin-3-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((7-chloroquinolin-3-yl)methyl)isonicotinamide(10 mg, 7%) was prepared as described in Example 24, Step 7 as a whitesolid. LRMS (M+H⁺) m/z calculated 432.2, found 432.2. ¹H NMR (CD₃OD, 400MHz) δ 8.87 (d, 1H), 8.63 (d, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.91 (d,1H), 7.78 (s, 1H), 7.63 (d, 1H), 7.60 (dd, 1H), 6.32 (s, 1H), 4.53 (d,2H), 4.44 (s, 2H), 2.41 (s, 3H), 2.29 (s, 3H).

Example 142: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide

To a solution of 2-(3-methyl-quinolin-6-ylmethyl)-isonicotinic acid (150mg, crude) in DMF (15 mL) was added 6-aminomethyl-isoquinolin-1-ylamine(62 mg, 0.36 mmol, 1.0 eq) followed by EDCI (104 mg, 0.54 mmol, 1.5 eq),HOBT (73 mg, 0.54 mmol, 1.5 eq) and TEA (109 mg, 1.08 mmol, 3.0 eq). Thereaction mixture was heated to 40° C. kept stirring for overnight. Waterwas added, and the mixture was extracted with DCM. The organic layer waswashed with water, dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by prep-HPLC to giveN-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide (30 mg, 19%) as a white solid. LRMS (M+H⁺) m/zcalculated 434, found 434.

¹H NMR (DMSO-d₆, 400 MHz) δ 9.40 (t, 1H), 8.71 (s, 1H), 8.67 (d, 1H),8.13 (d, 1H), 8.07 (s, 1H), 7.90 (d, 1H), 7.75-7.80 (m, 3H), 7.68 (d,1H), 7.62 (d, 1H), 7.54 (s, 1H), 7.49 (d, 1H), 6.84 (d, 1H), 6.77 (s,2H), 4.60 (d, 2H), 4.35 (s, 2H), 2.46 (s, 3H).

Example 143: Preparation ofN-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide

N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(30 mg, 18%) was prepared as described for Example 24, Step 7 as ayellow solid. LRMS (M+H+) m/z calculated 459, found 459. 1H NMR(DMSO-d₆, 300 MHz) δ 11.42 (br, 1H), 9.25 (t, 1H), 8.71 (s, 1H), 8.65(d, 1H), 8.05 (s, 1H), 7.89 (d, 1H), 7.76 (d, 2H), 7.60-7.66 (m, 2H),7.51 (d, 1H), 7.43 (d, 1H), 7.22 (d, 2H), 4.58 (d, 2H), 4.34 (s, 2H),2.46 (s, 3H).

Example 144: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide

To a solution of 2-(3-methyl-quinolin-6-ylmethyl)-isonicotinic acid (150mg, crude) in DMF (15 mL) was added5-aminomethyl-4,6-dimethyl-pyridin-2-ylamine dihydrochloride (400 mg,crude) followed by EDCI (104 mg, 0.54 mmol, 1.5 eq), HOBT (73 mg, 0.54mmol, 1.5 eq) and TEA (109 mg, 1.08 mmol, 3.0 eq). The reaction mixturewas heated to 40° C. kept stirring for overnight. Water was added, andthe mixture was extracted with DCM. The organic layer was washed withwater, dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by prep-HPLC to giveN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide(25 mg, 17%) as a yellow solid. LRMS (M+H⁺) m/z calculated 412, found412. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.71 (s, 1H), 8.65 (t, 1H), 8.60 (d,1H), 8.06 (s, 1H), 7.89 (d, 1H), 7.74 (d, 2H), 7.60 (d, 2H), 6.10 (s,1H), 5.70 (s, 2H), 4.32 (s, 4H), 2.46 (s, 3H), 2.29 (s, 3H), 2.15 (s,3H).

Example 145: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methylisoquinolin-6-yl)methyl)isonicotinamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methylisoquinolin-6-yl)methyl)isonicotinamide(29 mg, 21%) was prepared as described for Example 24, Step 7. LRMS(M+H⁺) m/z calculated 412.2, found 412.2. ¹H NMR (CD₃OD, 400 MHz) δ 9.05(s, 1H), 8.61 (d, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 7.69 (s, 1H), 7.62(dd, 1H), 7.55 (s, 1H), 7.52 (d, 1H), 6.30 (s, 1H), 4.49 (s, 2H), 4.38(s, 2H), 2.64 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H).

Example 146: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((2-(aminomethyl)quinolin-6-yl)methyl)isonicotinamide

Step 1: Preparation of tert-butyl(6-((4-((1-aminoisoquinolin-6-yl)methylcarbamoyl)pyridin-2-yl)methyl)quinolin-2-yl)methylcarbamate

tert-Butyl(6-((4-((1-aminoisoquinolin-6-yl)methylcarbamoyl)pyridin-2-yl)methyl)quinolin-2-yl)methylcarbamate(70 mg, 35%) was prepared as described for Example 24, Step 7.

Step 2: Preparation ofN-((1-aminoisoquinolin-6-yl)methyl)-2-((2-(aminomethyl)quinolin-6-yl)methyl)isonicotinamide

To a solution of tert-butyl(6-((4-((1-aminoisoquinolin-6-yl)methylcarbamoyl)pyridin-2-yl)methyl)quinolin-2-yl)methylcarbamate(80 mg, 0.13 mmol) in EtOAc (1 mL) was added HCl/EtOAc solution. Themixture was stirred at rt for 1 h. The precipitate was collected byfiltration to giveN-((1-aminoisoquinolin-6-yl)methyl)-2-((2-(aminomethyl)quinolin-6-yl)methyl)isonicotinamide (50 mg, 66%) as an off-white solid. LRMS (M+H⁺) m/zcalculated 449.2, found 449.2. ¹H NMR (DMSO-d₆, 400 MHz) δ 13.51 (s,1H), 10.05 (s, 1H), 9.25 (br, 1H), 8.88 (d, 1H), 8.63-8.62 (m, 4H), 8.45(d, 1H), 8.19 (s, 1H), 8.09-8.01 (m, 3H), 7.89 (d, 1H), 7.85 (s, 1H),7.73-7.64 (m, 4H), 7.20 (d, 1H), 4.69 (d, 2H), 4.59 (s, 2H), 4.39 (t,2H).

II. Biological Evaluation Example 1: In Vitro Enzyme Inhibition

The ability of the compounds disclosed herein to inhibit human plasmakallikrein activity was quantified according to the procedures below.

A 10 mM solution of the test compound was made in DMSO. This solutionwas serially diluted 1:5 in DMSO to yield 2000, 400, 80, 16, 3.2, 0.64,0.128, 0.0256 and 0.00512 μM compound test solutions. A control tubecontaining only DMSO is included. 16 μL of each compound test solutionwas combined with 384 μL of assay buffer (50 mM Tris-HCl pH 7.5, 150 mMNaCl, 0.01% Triton X-100) to yield a “4× test compound buffer stock”.

Separately, a 40 nM solution of human Plasma Kallikrein (Abcam) and a93.6 μM solution Pro-Phe-Arg-AMC (Bachem) were made using assay buffer.These solutions are hereby referred to as 4×hPK and 2×PFR-AMC,respectively.

60 μL of each 4× test compound buffer stock was combined with 600 μL, of4×hPK to yield 120 μL of “2× test compound buffer stock/2×hPK”. 50 μLwas removed from this mixture and placed into duplicate wells on aMicrofluor 1Black U-bottom microtiter plate (Thermo Scientific). Thisplate was incubated for 5 minutes at 37° C. To each well, 50 μL ofpre-warmed 2×PFR-AMC was added to start the enzymatic reaction. Cleavageof PFR-AMC was monitored in a Biotek Synergy H4 reader set at 37° C.Readings are taken every 43 seconds for 1 hour. The highest meanvelocity over 20 reads (˜15 minutes) is used to calculate the IC₅₀. TheIC₅₀ is calculated using the Gen5 (Biotek Instruments).

The ability of the compounds in Table 3 to inhibit human plasmakallikrein activity was determined.

TABLE 3 Chemical Synthesis hPK IC50 Example Name (μM) 16-((4-(((3-chloro-6-fluoro-1H-indol-5- Byl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2- carboxamide 26-((4-(((6-amino-2,4-dimethylpyridin-3- Byl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2- carboxamide 3N-((1-aminoisoquinolin-6-yl)methyl)-2-((2- Acyanoquinolin-6-yl)methyl)isonicotinamide 46-((4-(((1-aminoisoquinolin-6- Byl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-2- carboxamide 5N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Acyanoquinolin-6-yl)methyl)isonicotinamide 6N-((1-aminoisoquinolin-6-yl)methyl)-2-((3- Acyanoquinolin-6-yl)methyl)isonicotinamide 7N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Acyanoquinolin-6-yl)methyl)isonicotinamide 8N-((1-aminoisoquinolin-6-yl)methyl)-2-((7- Bfluoroquinoxalin-2-yl)methyl)isonicotinamide 92-((2-(acetamidomethyl)quinolin-6-yl)methyl)-N-((3- Bchloro-6-fluoro-1H-indol-5-yl)methyl)isonicotinamide 102-((2-(acetamidomethyl)quinolin-6-yl)methyl)-N-((1- Baminoisoquinolin-6-yl)methyl)isonicotinamide 112-((2-(acetamidomethyl)quinolin-6-yl)methyl)-N-((6- Bamino-2,4-dimethylpyridin-3-yl)methyl)isonicotinamide 12N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6- A(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide 13N-((1-aminoisoquinolin-6-yl)methyl)-2-((6- B(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide 14N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6- B(methylsulfonyl)quinolin-3-yl)methyl)isonicotinamide 15N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Amethyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide 16N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methyl-8- A(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide 17N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Amethyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide 18N-((6-fluoro-1H-indol-5-yl)methyl)-2-((3-methyl-8- A(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide 19N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2- A((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 20N-((5-chloro-1H-indazol-3-yl)methyl)-2-((3-methyl-8- A(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide 21N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((3- Amethyl-8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide 22N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5- Bchloro-1-oxoisoquinolin-2(1H)-yl)methyl)isonicotinamide 23N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6- Cchloro-1-oxoisoquinolin-2(1H)-yl)methyl)isonicotinamide 24N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Bchloro-1H-indol-5-yl)methyl)isonicotinamide 25N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Bmethyl-1H-indol-5-yl)methyl)isonicotinamide 26N-((6-amino-5-cyano-2-methylpyridin-3-yl)methyl)-2- C((3-chloroquinolin-6-yl)methyl)isonicotinamide 272-amino-5-((2-((3-chloroquinolin-6- Dyl)methyl)isonicotinamido)methyl)-6- methylnicotinamide 28N-((6-amino-5-chloro-2-methylpyridin-3-yl)methyl)-2- C((3-chloroquinolin-6-yl)methyl)isonicotinamide 29N-((6-amino-4-methylpyridin-3-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)isonicotinamide 30N-((6-amino-2-(trifluoromethyl)pyridin-3-yl)methyl)-2- D((3-chloroquinolin-6-yl)methyl)isonicotinamide 31N-((1-aminoisoquinolin-6-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)isonicotinamide 322-((3-chloroquinolin-6-yl)methyl)-N-((6-fluoro-1H- Cindazol-5-yl)methyl)isonicotinamide 33N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)isonicotinamide 34N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)isonicotinamide 35N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)isonicotinamide 36N-((3-aminobenzo[d]isoxazol-6-yl)methyl)-2-((3- Cchloroquinolin-6-yl)methyl)isonicotinamide 37N-((5-chloro-1H-indazol-3-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)isonicotinamide 38N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2- A((3-chloroquinolin-6-yl)methyl)isonicotinamide 39N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)isonicotinamide 40N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)isonicotinamide 412-((3-chloroquinolin-6-yl)methyl)-N-((6-fluoro-1H- Aindol-5-yl)methyl)isonicotinamide 422-((3-chloroquinolin-6-yl)methyl)-N-((2-methyl-6- B(methylamino)pyridin-3-yl)methyl)isonicotinamide 43N-((6-amino-2-cyclopropylpyridin-3-yl)methyl)-2-((3- Bchloroquinolin-6-yl)methyl)isonicotinamide 442-((3-chloroquinolin-6-yl)methyl)-N-((6- D(dimethylamino)-2-methylpyridin-3-yl)methyl)isonicotinamide 452-((2-(aminomethyl)quinolin-6-yl)methyl)-N-((3-chloro- B6-fluoro-1H-indol-5-yl)methyl)isonicotinamide 46N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2- A(aminomethyl)quinolin-6-yl)methyl)isonicotinamide 47N-((3-aminobenzo[d]isoxazol-6-yl)methyl)-2-((3- Cmethylquinolin-6-yl)methyl)isonicotinamide 48N-((3-aminobenzo[d]isoxazol-6-yl)methyl)-2-((6- Dmethylquinolin-3-yl)methyl)isonicotinamide 49N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Achloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide 50N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Achloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide 51N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((3- Achloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide 522-((3-chloro-8-cyanoquinolin-6-yl)methyl)-N-((6-fluoro- A1H-indol-5-yl)methyl)isonicotinamide 53N-((6-amino-4-methylpyridin-3-yl)methyl)-2-((3-chloro- B8-cyanoquinolin-6-yl)methyl)isonicotinamide 54N-((5-chloro-1H-indazol-3-yl)methyl)-2-((3-chloro-8- Acyanoquinolin-6-yl)methyl)isonicotinamide 55N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2- A((3-chloro-8-cyanoquinolin-6-yl)methyl)isonicotinamide 56N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro- A8-cyanoquinolin-6-yl)methyl)isonicotinamide 57N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8- Acyanoquinolin-6-yl)methyl)isonicotinamide 586-((4-(((6-amino-2,4-dimethylpyridin-3- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide 593-chloro-6-((4-(((3-chloro-6-fluoro-1H-indol-5- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8- carboxamide 603-chloro-6-((4-(((5-chloro-1H-indazol-3- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8- carboxamide 613-chloro-6-((4-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8- carboxamide 626-((4-(((6-amino-2-methylpyridin-3- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide 63 6-((4-(((6-amino-4-methylpyridin-3- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide 64 6-((4-(((1-aminoisoquinolin-6- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide 653-chloro-6-((4-(((3-chloro-4-fluoro-1H-indol-5- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8- carboxamide 663-chloro-6-((4-(((6-fluoro-1H-indol-5- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8- carboxamide 67N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Achloro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 68N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Achloro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 69N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro- A8-(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide 70N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((8- Acyano-3-methylquinolin-6-yl)methyl)isonicotinamide 71N-((1-aminoisoquinolin-6-yl)methyl)-2-((8-cyano-3- Amethylquinolin-6-yl)methyl)isonicotinamide 72N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((8- Acyano-3-methylquinolin-6-yl)methyl)isonicotinamide 73N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2- A((8-cyano-3-methylquinolin-6-yl)methyl)isonicotinamide 74N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((8- Acyano-3-methylquinolin-6-yl)methyl)isonicotinamide 75N-((5-chloro-1H-indazol-3-yl)methyl)-2-((8-cyano-3- Amethylquinolin-6-yl)methyl)isonicotinamide 762-((8-cyano-3-methylquinolin-6-yl)methyl)-N-((6-fluoro- A1H-indol-5-yl)methyl)isonicotinamide 776-((4-(((6-amino-2,4-dimethylpyridin-3- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 78 6-((4-(((3-chloro-6-fluoro-1H-indol-5-A yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 79 6-((4-(((1-aminoisoquinolin-6- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 806-((4-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 81 6-((4-(((3-chloro-4-fluoro-1H-indol-5-A yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 82 6-((4-(((5-chloro-1H-indazol-3- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 83 6-((4-(((6-fluoro-1H-indol-5- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 84 6-((4-(((6-amino-2,4-dimethylpyridin-3-A yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxylic acid 85N-((6-amino-4-methylpyridin-3-yl)methyl)-2-((7-chloro- B3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide 86N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((7-chloro- B3-oxoisoquinolin-2(3H)-yl)methyl)isonicotinamide 87N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((7- Bchloro-3-oxoisoquinolin-2(3H)- yl)methyl)isonicotinamide 882-((7-chloro-3-oxoisoquinolin-2(3H)-yl)methyl)-N-((3- Bchloro-6-fluoro-1H-indol-5-yl)methyl)isonicotinamide 89N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Achloro-8-fluoroquinolin-6-yl)methyl)isonicotinamide 90N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Achloro-8-fluoroquinolin-6-yl)methyl)isonicotinamide 91N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro- A8-fluoroquinolin-6-yl)methyl)isonicotinamide 92 methyl6-((4-(((6-amino-2,4-dimethylpyridin-3- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylate 93 6-((4-(((6-amino-2,4-dimethylpyridin-3-A yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylic acid 94N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Achloro-8-(hydroxymethyl)quinolin-6- yl)methyl)isonicotinamide 95 methyl6-((4-(((6-amino-2-methylpyridin-3- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxylate 96 6-((4-(((6-amino-2-methylpyridin-3- Byl)methyl)carbamoyl)pyridin-2-yl)methyl)-3- chloroquinoline-8-carboxylicacid 97 N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro- A8-(hydroxymethyl)quinolin-6-yl)methyl)isonicotinamide 986-amino-3-((2-((3-chloroquinolin-6- Byl)methyl)isonicotinamido)methyl)-2,4-dimethylpyridine 1-oxide 996-((4-(((6-amino-2,4-dimethylpyridin-3- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3- chloroquinoline 1-oxide 100N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3,8- Adichloroquinolin-6-yl)methyl)isonicotinamide 101N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3,8- Adichloroquinolin-6-yl)methyl)isonicotinamide 102N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Achloro-5-fluoroquinolin-6-yl)methyl)isonicotinamide 103N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3-chloro- A5-fluoroquinolin-6-yl)methyl)isonicotinamide 104N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)-6-methylisonicotinamide 105N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5- Achloro-1H-indazol-1-yl)methyl)isonicotinamide 106N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5- Achloro-2H-indazol-2-yl)methyl)isonicotinamide 107N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5- Bmethyl-2H-indazol-2-yl)methyl)isonicotinamide 108N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((5- Amethyl-1H-indazol-1-yl)methyl)isonicotinamide 109N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6- Bmethyl-2-(methylsulfonyl)quinolin-3- yl)methyl)isonicotinamide 110N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2- Amethylquinolin-6-yl)methyl)isonicotinamide 111N-((1-aminoisoquinolin-6-yl)methyl)-2-((2- Amethylquinolin-6-yl)methyl)isonicotinamide 112N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((2- Amethylquinolin-6-yl)methyl)isonicotinamide 113N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2- Amethylquinolin-6-yl)methyl)isonicotinamide 114N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6- Amethylquinolin-3-yl)methyl)isonicotinamide 115N-((1-aminoisoquinolin-6-yl)methyl)-2-((6- Amethylquinolin-3-yl)methyl)isonicotinamide 116N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6- Amethylquinolin-3-yl)methyl)isonicotinamide 117N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((6- Amethylquinolin-3-yl)methyl)isonicotinamide 118N-((1-aminoisoquinolin-6-yl)methyl)-2-((6- Afluoroquinolin-3-yl)methyl)isonicotinamide 119N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6- Afluoroquinolin-3-yl)methyl)isonicotinamide 120N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6- Afluoroquinolin-3-yl)methyl)isonicotinamide 121N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((6- Afluoroquinolin-3-yl)methyl)isonicotinamide 122N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((7- Afluoroquinolin-3-yl)methyl)isonicotinamide 123N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((7- Afluoroquinolin-3-yl)methyl)isonicotinamide 124N-((1-aminoisoquinolin-6-yl)methyl)-2-((7- Afluoroquinolin-3-yl)methyl)isonicotinamide 125N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2- A(quinolin-3-ylmethyl)isonicotinamide 126N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6- Achloroquinolin-3-yl)methyl)isonicotinamide 127N-((1-aminoisoquinolin-6-yl)methyl)-2-((2- Amethylquinolin-7-yl)methyl)isonicotinamide 128N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2- Amethylquinolin-7-yl)methyl)isonicotinamide 129N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2- Bmethylquinolin-7-yl)methyl)isonicotinamide 130N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2- Aisocyanoquinolin-6-yl)methyl)isonicotinamide 131N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2- Aisocyanoquinolin-6-yl)methyl)isonicotinamide 132N-((1-aminoisoquinolin-6-yl)methyl)-2-((3- Amethylisoquinolin-6-yl)methyl)isonicotinamide 133N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Amethylisoquinolin-6-yl)methyl)isonicotinamide 134N-((1-aminoisoquinolin-6-yl)methyl)-2-((2- B(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide 135N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2- B(methylsulfonyl)quinolin-6-yl)methyl)isonicotinamide 136N-((1-aminoisoquinolin-6-yl)methyl)-2-((4- Acyanoquinolin-6-yl)methyl)isonicotinamide 137N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((4- Bcyanoquinolin-6-yl)methyl)isonicotinamide 138N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((4- Acyanoquinolin-6-yl)methyl)isonicotinamide 139N-((1-aminoisoquinolin-6-yl)methyl)-2-((7- Achloroquinolin-3-yl)methyl)isonicotinamide 140N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((7- Achloroquinolin-3-yl)methyl)isonicotinamide 141N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((7- Achloroquinolin-3-yl)methyl)isonicotinamide 142N-((1-aminoisoquinolin-6-yl)methyl)-2-((3- Amethylquinolin-6-yl)methyl)isonicotinamide 143N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Amethylquinolin-6-yl)methyl)isonicotinamide 144N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Amethylquinolin-6-yl)methyl)isonicotinamide 145N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- Amethylisoquinolin-6-yl)methyl)isonicotinamide 146N-((1-aminoisoquinolin-6-yl)methyl)-2-((2- B(aminomethyl)quinolin-6-yl)methyl)isonicotinamide Note: Biochemicalassay IC₅₀ data are designated within the following ranges: A: ≤0.10 μMB: >0.10 μM to ≤1.0 μM C: >1.0 μM to ≤10 μM D: >10 μM

Example 2: In Vitro Cellular Assay

The ability of the compounds disclosed herein to inhibit cellularkallikrein activity was quantified and the respective EC₅₀ value wasdetermined.

Materials:

Plasma kallikrein inhibitor C1NH (Athens Research & Technology,Cat#16-16-031509); Ellagic acid (Sigma, E2250); Substrate Z-FR-2-AMC (GLBiochem, Cat#55352); Nunc™ 96-Well Polypropylene MicroWell™ Plates(Nunc, Cat#267342)

Methods:

All dilutions were prepared in an assay buffer comprising 50 mM Tris-HClpH 7.2, 150 mM NaCl, and 0.01% Triton X-100.

Four fold serial dilutions were prepared from a 107.53 μM plasmakallikrein inhibitor C1NH stock solution, to yield ten solutions withconcentrations between 20 μM and 0.76 nM. Similarly, four fold serialdilutions were prepared from 10 mM stock solutions of various testcompounds, to yield ten solutions with concentrations between 4 mM and0.015 μM. The ten solutions of the test compounds, prepared by serialdilution, were further diluted 50-fold in the assay buffer.

Human plasma is thawed on ice and centrifuged for 15 min at 4° C. toremove platelets. A 1 mM stock solution of ellagic acid is diluted to 8μM and mixed with human plasma, after removing platelets, at a ratio of1:0.8. The mixture of human plasma and ellagic acid was further diluted32-fold in the assay buffer, to yield the final mixture for use in theinhibition assay.

A 22.5 μL volume of the final mixture of human plasma and ellagic acidwas added to a 96-well microwell plate and the plate was incubated for15 min at 37° C.

The CINH inhibitor at various concentrations, prepared by serialdilutions as described above, were added to the inhibitor control wells.The volume of CINH inhibitor added to each inhibitor control well was12.5 μL, to yield final concentrations of 5 μM, 1.25 μM, 312.5 nM,78.125 nM, 19.531 nM, 4.883 nM, 1.221 nM, 0.305 nM, 0.076 nM, and 0.019nM. Each CINH concentration is tested in duplicates.

The test compounds at various concentrations, also prepared by serialdilutions as described above, are added to the test wells. The volume oftest compound added to each test well was 12.5 μL, to yield finalconcentrations of 20 μM, 5 μM, 1.25 μM, 312.5 nM, 78.125 nM, 19.531 nM,4.883 nM, 1.221 nM, 0.305 nM, and 0.076 nM. Each test compoundconcentration was tested in duplicates.

In addition to the inhibitor control and test wells, the 96 well assayplate includes positive control wells which contained the mixture ofhuman plasma and ellagic acid without C1NH inhibitor or test compounds,and background wells which contained neither the mixture of human plasmaand ellagic acid nor the test compounds. The total volume of liquid inpositive control and background wells was brought up to 35 μL, using theassay buffer.

The assay plate containing C1NH inhibitors and test compounds mixed withhuman plasma and ellagic acid and appropriate controls was incubated at37° C. for 5 mM. A 10 mM stock solution of substrate Z-FR-2-AMC wasdiluted to 133.2 μM in the assay buffer, and 15 μL of the dilutedsubstrate was added to each well, to yield a final substrateconcentration of 40 μM in each well. The reagents were mixed well byshaking the plate gently for 30 sec.

The enzyme reaction was quantified by immediate kinetic reading of theassay plate using excitation/emission wavelengths of 330 nm/440 nmrespectively. Fluorescence intensity was recorded for 60 mM, using atime interval of 43 sec.

The inhibition activity of the test compounds were evaluated using theIC50 values, calculated according to the dose-response curve of the testcompounds, fitted using the “log(inhibitor)-response(variable slope)”equation in GraphPadPrism software (GraphPad Software, Inc.).

The percentage inhibition was calculated using the following equation:

${{Inhibition}\mspace{25mu}\%} = {100 - {\frac{{{Sample}\mspace{14mu}{value}} - {{Mean}({BG})}}{{{Mean}({PC})} - {{Mean}({BG})}} \times 100}}$where, Mean(BG) is the average value of the fluorescence intensity ofthe background wells and Mean(PC) is the average value of thefluorescence intensity of the positive control wells.

Table 4 provides the EC₅₀ values of various compounds disclosed herein.

TABLE 4 Contact Chemical Assay Synthesis EC₅₀ Example Name (μM) 15N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2- A((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 16N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methyl- A8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 17N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Amethyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 18N-((6-fluoro-1H-indol-5-yl)methyl)-2-((3-methyl- B8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 19N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5- A yl)methyl)-2-((3-methyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 20N-((5-chloro-1H-indazol-3-yl)methyl)-2-((3- Amethyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 21N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((3- Amethyl-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 31N-((1-aminoisoquinolin-6-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)isonicotinamide 33N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Bchloroquinolin-6-yl)methyl)isonicotinamide 34N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)isonicotinamide 35N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2- A((3-chloroquinolin-6-yl)methyl)isonicotinamide 38N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5- Byl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide 39N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3- Achloroquinolin-6-yl)methyl)isonicotinamide 40N-((3-chloro-4-fluoro-1H-indol-5-yl)methyl)-2-((3- Bchloroquinolin-6-yl)methyl)isonicotinamide 50N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2- A((3-chloro-8-cyanoquinolin-6- yl)methyl)isonicotinamide 56N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3- Bchloro-8-cyanoquinolin-6- yl)methyl)isonicotinamide 57N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-chloro- B8-cyanoquinolin-6-yl)methyl)isonicotinamide 586-((4-(((6-amino-2,4-dimethylpyridin-3- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide 593-chloro-6-((4-(((3-chloro-6-fluoro-1H-indol-5- Byl)methyl)carbamoyl)pyridin-2- yl)methyl)quinoline-8-carboxamide 603-chloro-6-((4-(((5-chloro-1H-indazol-3- Byl)methyl)carbamoyl)pyridin-2- yl)methyl)quinoline-8-carboxamide 613-chloro-6-((4-(((3-chloro-1H-pyrrolo[2,3- Bb]pyridin-5-yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide 62 6-((4-(((6-amino-2-methylpyridin-3-A yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide 64 6-((4-(((1-aminoisoquinolin-6- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-chloroquinoline-8-carboxamide 653-chloro-6-((4-(((3-chloro-4-fluoro-1H-indol-5- Ayl)methyl)carbamoyl)pyridin-2- yl)methyl)quinoline-8-carboxamide 663-chloro-6-((4-(((6-fluoro-1H-indol-5- B yl)methyl)carbamoyl)pyridin-2-yl)methyl)quinoline-8-carboxamide 67N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2- A((3-chloro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 68N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Achloro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 69N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3- Achloro-8-(methylsulfonyl)quinolin-6- yl)methyl)isonicotinamide 70N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2- A((8-cyano-3-methylquinolin-6- yl)methyl)isonicotinamide 71N-((1-aminoisoquinolin-6-yl)methyl)-2-((8-cyano- A3-methylquinolin-6-yl)methyl)isonicotinamide 72N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((8- Bcyano-3-methylquinolin-6- yl)methyl)isonicotinamide 73N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5- Byl)methyl)-2-((8-cyano-3-methylquinolin-6- yl)methyl)isonicotinamide 776-((4-(((6-amino-2,4-dimethylpyridin-3- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 78 6-((4-(((3-chloro-6-fluoro-1H-indol-5-A yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 79 6-((4-(((1-aminoisoquinolin-6- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 806-((4-(((3-chloro-1H-pyrrolo[2,3-b]pyridin-5- Ayl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 81 6-((4-(((3-chloro-4-fluoro-1H-indol-5-B yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 82 6-((4-(((5-chloro-1H-indazol-3- Byl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 83 6-((4-(((6-fluoro-1H-indol-5- Byl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxamide 84 6-((4-(((6-amino-2,4-dimethylpyridin-3-A yl)methyl)carbamoyl)pyridin-2-yl)methyl)-3-methylquinoline-8-carboxylic acid 89N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2- A((3-chloro-8-fluoroquinolin-6- yl)methyl)isonicotinamide 91N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((3- Achloro-8-fluoroquinolin-6- yl)methyl)isonicotinamide 100N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2- A((3,8-dichloroquinolin-6-yl)methyl)isonicotinamide 110N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((2- Bmethylquinolin-6-yl)methyl)isonicotinamide 111N-((1-aminoisoquinolin-6-yl)methyl)-2-((2- Bmethylquinolin-6-yl)methyl)isonicotinamide 113N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2- A((2-methylquinolin-6-yl)methyl)isonicotinamide 114N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2- A((6-methylquinolin-3-yl)methyl)isonicotinamide 115N-((1-aminoisoquinolin-6-yl)methyl)-2-((6- Amethylquinolin-3-yl)methyl)isonicotinamide 116N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((6- Bmethylquinolin-3-yl)methyl)isonicotinamide 117N-((6-amino-2-methylpyridin-3-yl)methyl)-2-((6- Bmethylquinolin-3-yl)methyl)isonicotinamide 118N-((1-aminoisoquinolin-6-yl)methyl)-2-((6- Afluoroquinolin-3-yl)methyl)isonicotinamide 132N-((1-aminoisoquinolin-6-yl)methyl)-2-((3- Bmethylisoquinolin-6-yl)methyl)isonicotinamide 142N-((1-aminoisoquinolin-6-yl)methyl)-2-((3- Amethylquinolin-6-yl)methyl)isonicotinamide 143N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3- Bmethylquinolin-6-yl)methyl)isonicotinamide 144N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2- A((3-methylquinolin-6-yl)methyl)isonicotinamide 145N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2- A((3-methylisoquinolin-6-yl)methyl)isonicotinamide Note: Assay EC₅₀ dataare designated within the following ranges: A: ≤0.10 μM B: >0.10 μM to≤1.0 μM C: >1.0 μM to ≤10 μM D: >10 μM

III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral Tablet

A tablet is prepared by mixing 48% by weigh of a compound of Formula (I)or a pharmaceutically acceptable salt thereof, 45% by weight ofmicrocrystalline cellulose, 5% by weight of low-substitutedhydroxypropyl cellulose, and 2% by weight of magnesium stearate. Tabletsare prepared by direct compression. The total weight of the compressedtablets is maintained at 250-500 mg.

We claim:
 1. A compound of Formula IIb:

wherein: C is a bicyclic 8-12 membered heteroaryl ring selected from the group consisting of indole, quinoline, isoquinoline, and quinazoline that is optionally substituted with one or more groups independently selected from halo, cyano, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, —(C₁-C₆)alkyl-COOH, —NR^(a)R^(b), S(═O)₂R^(e), and —C(═O)NR^(a)R^(b); D is CH₂; X₁ is CH and X₄ is N, or X₁ is N and X₄ is CH; X₂ is CH; X₃ is CH; G is CH₂; J is pyridine, indole, or indazole that is optionally substituted with one or more groups independently selected from halo, (C₁-C₆)alkyl, —NR^(a)R^(b); each R^(a) is independently H or (C₁-C₆)alkyl; each R^(b) is independently H or (C₁-C₆)alkyl; and each R^(e) is independently H or (C₁-C₆)alkyl; or a salt thereof.
 2. The compound of claim 1, wherein C is indole, quinoline, isoquinoline, or quinazoline that is optionally substituted with one or more groups independently selected from F, Cl, CN, CH₃, OCH₃, —CH₂C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂, and —S(═O)₂CH₃.
 3. The compound of claim 2, wherein C is selected from the group consisting of


4. The compound of claim 3, wherein C is


5. The compound of 1, wherein X₁ is CH and X₄ is N.
 6. The compound of 1, wherein X₁ is N and X₄ is CH.
 7. The compound of 1, wherein J is pyridine, indole, indazole, or isoquinoline that is optionally substituted with one or more groups independently selected from F, Cl, CH₃, and NH₂.
 8. The compound of claim 7, wherein J is selected from the group consisting of


9. The compound of claim 8, wherein J is


10. The compound of claim 8, wherein J is


11. A compound wherein the compound is: N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((6-methylquinolin-3-yl)methyl)isonicotinamide; N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide; N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((2-methylquinolin-6-yl)methyl)isonicotinamide; N-((1-aminoisoquinolin-6-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide; or N-((3-chloro-6-fluoro-1H-indol-5-yl)methyl)-2-((3-methylquinolin-6-yl)methyl)isonicotinamide; or a salt thereof.
 12. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 13. A method of treating angioedema in a patient in need thereof comprising administering to the patient a composition of claim 1, or a pharmaceutically acceptable salt thereof.
 14. The method of claim 11 wherein the angioedema is hereditary angioedema.
 15. A method of treating macular edema in a patient in need thereof comprising administering to the patient a composition of claim 1, or a pharmaceutically acceptable salt thereof.
 16. A method of treating brain edema in a patient in need thereof comprising administering to the patient a composition of claim 1, or a pharmaceutically acceptable salt thereof. 